Substituted 7-azabicycles and their use as orexin receptor modulators

ABSTRACT

The present invention is directed to compounds of Formula I: 
                         
wherein A is phenyl, naphthalenyl, pyridyl, quinolinyl, isoquinolinyl, imidazopyridyl, furanyl, thiazolyl, isoxazolyl, pyrazolyl, imidazothiazolyl, benzimidazolyl, or indazolyl; R 1  is H, alkyl, alkoxy, hydroxyalkylene, OH, halo, phenyl, triazolyl, oxazolyl, isoxazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, piperazinyl, pyrazolyl, oxadiazolyl, pyrrolidinyl, thiophenyl, morpholinyl, or dialkylamino; R 2  is H, alkyl, alkoxy, hydroxyalkylene, or halo; Z is NH, N-alkyl, or O; R 5  is pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, quinazolinyl, quinoxalinyl, pyrazolyl, benzoxazolyl, imidazopyrazinyl, or triazolopyrazinyl, optionally substituted with a one or two substituents independently selected from the group consisting of alkyl, alkoxy, or halo; and n is 0 or 1. Methods of making the compounds of Formula I are also described. The invention also relates to pharmaceutical compositions comprising compounds of Formula I. Methods of using the compounds of the invention are also within the scope of the invention.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No. 14/718,327, filed May 21, 2015, which is a divisional of U.S. patent application Ser. No. 14/206,764, filed Mar. 12, 2014, now U.S. Pat. No. 9,062,078, which claims the benefit of U.S. Provisional Patent Application No. 61/780,428, filed Mar. 13, 2013, the entire disclosures of which are incorporated herein by reference in their entirety.

TECHNICAL FIELD

The present invention is directed to substituted 7-azabicyclic compounds, pharmaceutical compositions comprising them, methods of making them, and methods of using them for the modulation of the orexin receptor for the treatment of disease states, disorders, and conditions mediated by orexin receptor activity.

BACKGROUND

Orexin/hypocretin signaling is mediated by two receptors and two peptide agonists. The peptides (orexin-A and orexin-B) are cleavage products of the same gene, pre-pro orexin. In the central nervous system, neurons producing pre-pro orexin are found solely in the perifornical nucleus, the dorsal hypothalamus, and the lateral hypothalamus (Peyron et al., 1998, J. Neurosci. 18: 9996-10015). Orexigenic cells in these regions project to many areas of the brain, extending rostrally to the olfactory bulbs and caudally to the spinal cord (Van den Pol, 1999, J. Neurosci. 19: 3171-3182).

The orexins bind to two high affinity receptors, referred to as orexin-1 and orexin-2 receptors. Orexin-1 and orexin-2 receptors are G-protein-coupled, seven transmembrane receptors that share over 64% amino acid sequence identity with one another. Both receptors are generally excitatory, the common cellular response to orexin-induced receptor activation being increases in intracellular calcium. Homology between the species orthologs is high and there are no known pharmacological differences. Orexin-A and -B are usually considered equal ligands for orexin-2 receptor but orexin-B is thought to be 5- to 100-fold weaker ligand than orexin-A at the orexin-1 receptor (Sakurai et al., 1998, Cell 92: 573-585; Ammoun et al., 2003, J. Pharmacol. Exp. Ther. 305: 507-514).

Many regions of the brain have fairly selective expression of the orexin-1 or orexin-2 receptors (Marcus et al., 2001, 1 Comp Neurology 435, 6-25; Trivedi et al., 1998, FEBS Letters, 438, 71-75). Orexin-1 receptors are selective for the limbic system (bed nucleus of the stria terminalis and amygdala), cingulate cortex and noradrenergic neurons in the locus coeruleus. Conversely, the orexin-2 receptor is almost the exclusive orexin receptor in the histaminergic neurons in the tuberomammilary nucleus which play a critical role in wake promotion; in paraventricular neurons and the parabrachial nucleus. In other brain regions like the dorsal raphe, the ventral tegmental area or the prefontal cortex both receptors are coexpressed.

The broad CNS distribution of cells producing orexin, as well as cells expressing the orexin receptors, suggests involvement of orexin in a number of physiological functions, including feeding and metabolism, regulation of wakefulness and sleep, sympathetic activation and stress response (de Lecea, 2012, Progress in Brain Research, 198, 15-24; Kukkonen, 2013, Am J. Physiol. Cell Physiol., 304, C2-C32). Orexin also plays a key role regulating motivation and reward associated with food intake and with drugs of abuse (Mahler et al., 2012, Progress in Brain Research, 198, 79-121).

Several lines of evidence indicate that the orexin system is an important modulator of arousal. Rodents administered orexin intracerebroventricularly spend more time awake (Piper et al., 2000, J. Neurosci. 12: 726-730. Orexin-mediated effects on arousal have been linked to orexin neuronal projections to histaminergic neurons in the tuberomammillary nucleus (Yamanaka et al., 2002, Biochem. Biophys. Res. Comm. 290: 1237-1245). Rodents whose pre-pro orexin gene has been knocked out, or whose orexigenic neurons have been killed, display altered sleep/wake cycles similar to narcolepsy (Chemelli et al., 1999, Cell 98: 437-451; Hara et al., 2001, Neuron 30: 345-354). Dog models of narcolepsy have been shown to have mutant or non-functional orexin-2 receptors (Lin et al., 1999, Cell 98: 365-376). Orexin signaling as a target for sleep-promoting therapies was further validated clinically by findings of attenuated orexin levels and loss of orexinergic neurons in human narcoleptic patients (Mignot et al., 2001, Am. J. Hum. Genet. 68: 686-699; Minot & Thorsby, 2001, New England J. Med. 344: 692) or, in rare cases, to mutations in the orexin-2 gene (Peyron et al., 2000, Nature Med. 6: 991-997). Disorders of the sleep-wake cycle are therefore likely targets for orexin-2 receptor modulator activity. Examples of sleep-wake disorders that may be treated by agonists or other modulators that up-regulate orexin-2 receptor-mediated processes include narcolepsy, jet lag (sleepiness) and sleep disorders secondary to neurological disorders such as depression. Examples of disorders that may be treated by antagonists or other modulators that down-regulate orexin-2 receptor-mediated processes include insomnia, restless leg syndrome, jet lag (wakefulness) and sleep disorders secondary to neurological disorders such as mania, schizophrenia, pain syndromes and the like.

Evidence has accumulated to demonstrate a clear involvement of orexin signaling in reward pathways associated with drug dependence (Mahler et al., 2012, Progress in Brain Research, 198, 79-121). Orexinergic neurons send projections to the ventral tegmental area and other brain regions involved in reward processing. Orexin ligands mediate reward behavior, and antagonizing these effects with a selective orexin-1 receptor antagonist in various preclinical model of addiction has suggested that these actions are mediated through orexin-1 receptor. Specifically, a selective orexin-1 antagonist attenuates morphine conditioned place preference and reinstatement (Harris et al., 2005, Nature, 437, 556-5599; Narita et al., 2006, J Neurosci., 26, 398-405; Harris et al., 2007, Behav Brain Res, 183, 43-51), stress-induced cocaine reinstatement, cocaine-induced behavioral and synaptic plasticity (Borgland et al., 2006, Neuron, 49, 589-601), and intake and cue and stress-induced reinstatement of ethanol (Lawrence et al., 2006, Br J Pharmacol, 148, 752-759), in addition to attenuating precipitated morphine withdrawal (Sharf et al., 2008, Biol Psychiatry, 64, 175-183) and nicotine self-administration (Hollander et al., 2008, Proc Natl Acad Sci USA., 105, 19480-19485). Another recent study has also suggested a role for OX2R (Shoblock et al., 2011, Psychopharmacology, 215, 191-203).

Orexin's role in more complex emotional behavior is also emerging (Johnson et al., 2012, Progress in Brain Research, 198, 133-161). Changes in orexin levels in patients with panic and posttraumatic stress disorders have been noted as have changes in the prevalence of anxiety behaviors in narcoleptic patients (Johnson et al., 2010, Nature Medicine, 16, 111-115; Fortuyn et al., 2010, General Hospital Psychiatry, 32, 49-56; Strawn et al., 2010, Psychoneuroendocrinology, 35, 1001-1007). Lactate infusion or acute hypercapnia, which causes panic in humans, and are used as an animal model of panic, activates orexin neurons in the perifornical hypothalamus. This activation correlates with anxiety in the social interaction test or open field test. Blocking orexin signaling with either siRNA or selective orexin-1 receptor antagonists attenuates panic-like responses to lactate (Johnson et al., 2010, Nature Medicine, 16, 111-115; Johnson et al., 2012, Neuropsychopharmacology, 37, 1911, 1922).

Cerebral spinal fluid (CSF) levels of orexin are lower in depressed or suicidal patients, and the level of orexin inversely correlates with illness severity (Brundin et al., 2007, European Neuropsychopharmacology, 17, 573-579; Salomon et al., 2003, Biol Psychiatry, 54, 96-104). A positive correlation between orexin-1 receptor mRNA in the amygdala and depressive behavior in the forced swim test in mice has been reported (Arendt, 2013, Behavioral Neuroscience, 127, 86-94).

The orexin system also interacts with brain dopamine systems. Intracerebroventricular injections of orexin in mice increase locomotor activity, grooming and stereotypy; these behavioral effects are reversed by administration of D2 dopamine receptor antagonists (Nakamura et al., 2000, Brain Res. 873: 181-187). Therefore, orexin receptor modulators may be useful to treat various neurological disorders; e.g., agonists or up-regulators to treat catatonia, antagonists or down-regulators to treat Parkinson's disease, Tourette's syndrome, anxiety, delirium and dementias.

Orexins and their receptors have been found in both the myenteric and submucosal plexus of the enteric nervous system, where orexins have been shown to increase motility in vitro (Kirchgessner & Liu, 1999, Neuron 24: 941-951) and to stimulate gastric acid secretion in vitro (Takahashi et al., 1999, Biochem. Biophys. Res. Comm. 254: 623-627). Orexin effects on the gut may be driven by a projection via the vagus nerve (van den Pol, 1999, supra), as vagotomy or atropine prevent the effect of an intracerebroventricular injection of orexin on gastric acid secretion (Takahashi et al., 1999, supra). Orexin receptor antagonists or other down-regulators of orexin receptor-mediated systems are therefore potential treatments for ulcers, irritable bowel syndrome, diarrhea and gastroesophageal reflux.

Body weight may also be affected by orexin-mediated regulation of appetite and metabolism. Some effects of orexin on metabolism and appetite may be mediated in the gut, where, as mentioned, orexins alter gastric motility and gastric acid secretion. Orexin antagonists therefore are likely to be useful in treatment of overweight or obesity and conditions related to overweight or obesity, such as insulin resistance/type II diabetes, hyperlipidemia, gallstones, angina, hypertension, breathlessness, tachycardia, infertility, sleep apnea, back and joint pain, varicose veins and osteoarthritis. Conversely, orexin agonists are likely to be useful in treatment of underweight and related conditions such as hypotension, bradycardia, amenorrhea and related infertility, and eating disorders such as anorexia and bulimia.

Intracerebroventricularly administered orexins have been shown to increase mean arterial pressure and heart rate in freely moving (awake) animals (Samson et al., 1999, Brain Res. 831: 248-253; Shirasaka et al., 1999, Am. J. Physiol. 277: R1780-R1785) and in urethane-anesthetized animals (Chen et al., 2000, Am. J. Physiol. 278: R692-R697), with similar results. Orexin receptor agonists may therefore be candidates for treatment of hypotension, bradycardia and heart failure related thereto, while orexin receptor antagonists may be useful for treatment of hypertension, tachycardia and other arrhythmias, angina pectoris and acute heart failure.

From the foregoing discussion, it can be seen that the identification of orexin receptor modulators, will be of great advantage in the development of therapeutic agents for the treatment of a wide variety of disorders that are mediated through these receptor systems.

SUMMARY

The present invention is directed to compounds of Formula I:

wherein ring A is phenyl, naphthalenyl, pyridyl, quinolinyl, isoquinolinyl, imidazopyridyl, furanyl, thiazolyl, isoxazolyl, pyrazolyl, imidazothiazolyl, benzimidazolyl, or indazolyl; R₁ is H, alkyl, alkoxy, hydroxyalkylene, OH, halo, phenyl, triazolyl, oxazolyl, isoxazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, piperazinyl, pyrazolyl, oxadiazolyl, pyrrolidinyl, thiophenyl, morpholinyl, or dialkylamino; R₂ is H, alkyl, alkoxy, hydroxyalkylene, or halo; Z is NH, N-alkyl, or O; R₅ is pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, quinazolinyl, quinoxalinyl, pyrazolyl, benzoxazolyl, imidazopyrazinyl, triazolopyrazinyl, optionally substituted with a one or two substituents independently selected from the group consisting of alkyl, alkoxy, or halo; and n is 0 or 1. Enantiomers and diastereomers of the compounds of Formula I are also described, as well as the pharmaceutically acceptable salts.

Methods of making the compounds of Formula I are also described. The invention also relates to pharmaceutical compositions comprising compounds of Formula I. Methods of using the compounds of the invention are also within the scope of the invention.

DETAILED DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS

The invention may be more fully appreciated by reference to the following description, including the following glossary of terms and the concluding examples.

The term “alkyl” refers to a straight- or branched-chain alkyl group having from 1 to 12 carbon atoms in the chain. Examples of alkyl groups include methyl (Me) ethyl (Et), n-propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl (tBu), pentyl, isopentyl, tert-pentyl, hexyl, isohexyl, and groups that in light of the ordinary skill in the art and the teachings provided herein would be considered equivalent to any one of the foregoing examples. Alkyl groups of the invention can be optionally substituted with, for example, one or more halogen atoms. One exemplary substituent is fluoro. Preferred substituted alkyl groups of the invention include trihalogenated alkyl groups such as trifluoromethyl groups.

Alkyl groups of the invention can also refer to “cycloalkyl” moieties. Cycloalkyl refers to monocyclic, non-aromatic hydrocarbon groups having from 3 to 7 carbon atoms. Examples of cycloalkyl groups include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 1-methylcyclopropyl, 2-methylcyclopentyl, and the like.

The term “alkoxy” includes a straight chain or branched alkyl group with a terminal oxygen linking the alkyl group to the rest of the molecule. Alkoxy includes methoxy, ethoxy, propoxy, isopropoxy, butoxy, t-butoxy, pentoxy and so on. Alkoxy groups of the inventions can be optionally substituted with, for example, one or more halogen atoms (haloalkoxy). One exemplary substitutent is fluoro. Preferred substituted alkoxy groups of the invention are substituted with one, two, or three halogen atoms, for example, —OCHCF₂.

The term “amino” represents NH₂. The term “dialkylamino” represents the moiety wherein each H of the amino group is replaced by an alkyl group. These alkyl groups ca be the same or different. Preferred alkyl groups are the C₁₋₆alkyl groups. Examples of dialkyl amino groups include dimethylamino, diethylamino, diisopropylamino, and the like. Other examples include methylethylamino, methylisopropylamino, and the like.

The term “aryl ring” represents” a mono- or bi-cyclic aromatic, hydrocarbon ring structure. Aryl rings can have 6 or 10 carbon atoms in the ring.

The term “benzimidazolyl” represents the following moiety:

The benzimidazolyl moiety can be attached through any one of the 1-, 2-, 3-, 4-, 5-, 6-, or 7-position atoms.

The term “benzoxazolyl” represents the following moiety:

The benoxazolyl moiety can be attached through any one of the 2-, 4-, 5-, 6-, or 7-position carbon atoms.

The term “furanyl” represents the following moiety:

The furanyl moiety can be attached through any one of the 2-, 3-, 4-, or 5-position carbon atoms.

The term “halogen” represents chlorine, fluorine, bromine, or iodine. The term “halo” represents chloro, fluoro, bromo, or iodo.

The term “heteroaryl ring” represents a mono- or bicyclic aromatic ring structure including carbon atoms as well as up to four heteroatoms selected from nitrogen, oxygen, and sulfur. Heteroaryl rings can include a total of 5, 6, 9, or 10 ring atoms.

The term “hydroxyalkylene” represents an alkyl group, terminally substituted with OH. Examples of hydroxyalkylene moieties include —CH₂—OH, —CH₂CH₂—OH, —CH₂CH₂CH₂—OH, and the like.

The term “imidazopyridyl” represents the following moiety:

The imidazopyridyl moiety can be attached through any one of the 2-, 3-, 4-, 5-, 6-, or 7-position carbon atoms.

The term “imidazopyrazinyl” represents the following moiety:

The imidazopyrazinyl moiety can be attached through any one of the 2-, 5-, or 6-position carbon atoms.

The term “imidazothiazolyl” represents the following moiety:

The imidazothiazolyl moiety can be attached through any one of the 2-, 3-, 5-, or 6-position carbon atoms.

The term “indazolyl” represents the following moiety:

The indazolyl moiety can be attached through any one of the 1-, 3-, 4-, 5-, 6-, or 7-position atoms.

The term “isoquinolinyl” represents the following moiety:

The isoquinolinyl moiety can be attached through any one of the 1-, 3-, 4-, 5-, 6-, 7-, or 8-position carbon atoms.

The term “isoxazolyl” represents the following moiety:

The isoxazolyl moiety can be attached through any one of the 3-, 4-, or 5-position carbon atoms. Isoxazolyl groups of the invention can be optionally substituted with, for example, one or two alkyl groups, for example, one or two methyl groups.

The term “naphthalenyl” represents the following moiety:

The naphthalenyl moiety can be attached through any one of the 1-, 2-, 3-, 4-, 5-, 6-, 7-, or 8-position carbon atoms.

The term “morpholinyl” represents the following moiety:

The 4-position nitrogen atom may be substituted with H or alkyl, for example methyl. The 4-position nitrogen can also be protected with a nitrogen protecting group such as a butyl-oxycarbonyl (-Boc). The morpholinyl moiety can be attached through any one of the 2-, 3-, 4-, 5-, or 6-position atoms.

The term “oxazolyl” represents the following moiety:

The oxazolyl moiety can be attached through any one of the carbon atoms. Oxazolyl groups of the invention can be optionally substituted with, for example, one or two alkyl groups, for example, one or two methyl groups.

The term “oxadiazolyl” represents a 1,2,3-oxadiazole, 1,2,4-oxadiazole, 1,2,5-oxadiazole, or 1,3,4-oxadiazole moiety:

The oxadiazolyl moieties can be attached through any one of the carbon or nitrogen atoms. Within the scope of the invention, “oxadiazolyl” groups can be substituted with an alkyl group, preferably a methyl group.

The term “phenyl” represents the following moiety:

Phenyl groups of the inventions can be optionally substituted with, for example, one or more halogen atoms (halo-phenyl). Exemplary substituents are fluoro, bromo, and chloro. Preferred substituted phenyl groups of the invention are substituted with one, two, or three halogen atoms.

The term “pyridyl” represents the following moiety:

The pyridyl moiety can be attached through any one of the 2-, 3-, 4-, 5-, or 6-position carbon atoms. Pyridyl groups of the invention can be optionally substituted with, for example, one or more alkyl groups, for example, one or two methyl groups.

The term “piperazinyl” represents the following moiety:

The piperazinyl moiety can be attached through any one of the 1-, 2-, 3-, 4-, 5-, or 6-position atoms. Any one of the nitrogen atoms of the piperazinyl moiety can be substituted with H or alkyl, for example, methyl.

The term “pyrimidinyl” represents the following moiety:

The pyrimidinyl moiety can be attached through any one of the 2-, 4-, 5-, or 6-position carbon atoms. Within the scope of the invention, “pyrimidinyl” groups of the invention can be substituted with halogen, for example fluoro.

The term “pyrazinyl” represents the following moiety:

The pyrazinyl moiety can be attached through any one of the 2-, 3-, 5-, or 6-position carbon atoms.

The term “pyridazinyl” represents the following moiety:

The pyridazinyl moiety can be attached through any one of the 3-, 4-, 5-, or 6-position carbon atoms.

The term “pyrazolyl” represents the following moiety:

The pyrazolyl moiety can be attached through any one of the 1-, 2-, 3-, 4-, or 5-position carbon atoms. Pyrazolyl groups of the invention can be optionally substituted with, for example, one or two alkyl groups, for example, one or two methyl groups.

The term “pyrrolidinyl” represents the following moiety:

The pyrrolidinyl moiety can be attached through any one of the 1-, 2-, 3-, 4-, or 5-position atoms. When the pyrrolidinyl moiety is not attached through the 1-position nitrogen, the nitrogen can be substituted with H or alkyl, for example methyl.

The term “quinolinyl” represents the following moiety:

The quinolinyl moiety can be attached through any one of the 2-, 3-, 4-, 5-, 6-, 7-, or 8-position carbon atoms.

The term “quinoxalinyl” represents the following moiety:

The quinoxalinyl moiety can be attached through any one of the 2-, 3-, 5-, 6-, 7-, or 8-position carbon atoms.

The term “quinazolinyl” represents the following moiety:

The quinoxalinyl moiety can be attached through any one of the 2-, 4-, 5-, 6-, 7-, or 8-position carbon atoms.

The term “thiazolyl” represents the following moiety:

The thiazolyl moiety can be attached through any one of the 2-, 4-, or 5-position carbon atoms.

The term “thiophenyl” represents the following moiety:

The thiophenyl moiety can be attached through any one of the 2-, 3-, 4-, or 5-position carbon atoms.

The term “triazolopyrazinyl” represents the following moiety:

The triazolopyrazinyl moiety can be attached through any one of the 1-, 3-, 4-, 5-, 6-, or 7-position atoms.

The term “triazolyl” represents a 1,2,3-triazole or a 1,2,4-triazole moiety:

The triazolyl moieties can be attached through any one of their atoms.

“Pharmaceutically acceptable” means approved or approvable by a regulatory agency of the Federal or a state government or the corresponding agency in countries other than the United States, or that is listed in the U.S. Pharmacopoeia or other generally recognized pharmacopoeia for use in animals, and more particularly, in humans.

“Pharmaceutically acceptable salt” refers to a salt of a compound of the invention that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent compound. In particular, such salts are non-toxic may be inorganic or organic acid addition salts and base addition salts. Specifically, such salts include: (1) acid addition salts, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo[2.2.2]-oct-2-ene-1-carboxylic acid, glucoheptonic acid, 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, and the like; or (2) salts formed when an acidic proton present in the parent compound either is replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion; or coordinates with an organic base such as ethanolamine, diethanolamine, triethanolamine, N-methylglucamine and the like. Salts further include, by way of example only, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, and the like; and when the compound contains a basic functionality, salts of non toxic organic or inorganic acids, such as hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, oxalate and the like.

“Pharmaceutically acceptable vehicle” refers to a diluent, adjuvant, excipient or carrier with which a compound of the invention is administered. A “pharmaceutically acceptable excipient” refers to a substance that is non-toxic, biologically tolerable, and otherwise biologically suitable for administration to a subject, such as an inert substance, added to a pharmacological composition or otherwise used as a vehicle, carrier, or diluent to facilitate administration of agent and that is compatible therewith. Examples of excipients include calcium carbonate, calcium phosphate, various sugars and types of starch, cellulose derivatives, gelatin, vegetable oils, and polyethylene glycols.

“Subject” includes humans. The terms “human,” “patient,” and “subject” are used interchangeably herein.

“Treating” or “treatment” of any disease or disorder refers, in one embodiment, to ameliorating the disease or disorder (i.e., arresting or reducing the development of the disease or at least one of the clinical symptoms thereof). In another embodiment “treating” or “treatment” refers to ameliorating at least one physical parameter, which may not be discernible by the subject. In yet another embodiment, “treating” or “treatment” refers to modulating the disease or disorder, either physically, (e.g., stabilization of a discernible symptom), physiologically, (e.g., stabilization of a physical parameter), or both. In yet another embodiment, “treating” or “treatment” refers to delaying the onset of the disease or disorder.

“Compounds of the present invention,” and equivalent expressions, are meant to embrace compounds of the Formula (I) as described herein, which expression includes the pharmaceutically acceptable salts, and the solvates, e.g., hydrates, where the context so permits. Similarly, reference to intermediates, whether or not they themselves are claimed, is meant to embrace their salts, and solvates, where the context so permits.

As used herein, the term “isotopic variant” refers to a compound that contains unnatural proportions of isotopes at one or more of the atoms that constitute such compound. For example, an “isotopic variant” of a compound can be radiolabeled, that is, contain one or more non-radioactive isotopes, such as for example, deuterium (²H or D), carbon-13 (¹³C), nitrogen-15 (¹⁵N), or the like. It will be understood that, in a compound where such isotopic substitution is made, the following atoms, where present, may vary, so that for example, any hydrogen may be ²H/D, any carbon may be ¹³C, or any nitrogen may be ¹⁵N, and that the presence and placement of such atoms may be determined within the skill of the art. Likewise, the invention may include the preparation of isotopic variants with radioisotopes, in the instance for example, where the resulting compounds may be used for drug and/or substrate tissue distribution studies. Radiolabeled compounds of the invention can be used in diagnostic methods such as Single-photon emission computed tomography (SPECT). The radioactive isotopes tritium, i.e. ³H, and carbon-14, i.e. ¹⁴C, are particularly useful for their ease of incorporation and ready means of detection. Further, compounds may be prepared that are substituted with positron emitting isotopes, such as ¹¹C, ¹⁸F, ¹⁵O and ¹³N, and would be useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy.

All isotopic variants of the compounds of the invention, radioactive or not, are intended to be encompassed within the scope of the invention.

It is also to be understood that compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space are termed “isomers.” Isomers that differ in the arrangement of their atoms in space are termed “stereoisomers.”

Stereoisomers that are not mirror images of one another are termed “diastereomers” and those that are non-superimposable mirror images of each other are termed “enantiomers.” When a compound has an asymmetric center, for example, it is bonded to four different groups, a pair of enantiomers is possible. An enantiomer can be characterized by the absolute configuration of its asymmetric center and is described by the R- and S-sequencing rules of Cahn and Prelog, or by the manner in which the molecule rotates the plane of polarized light and designated as dextrorotatory or levorotatory (i.e., as (+) or (−)-isomers respectively). A chiral compound can exist as either individual enantiomer or as a mixture thereof. A mixture containing equal proportions of the enantiomers is called a “racemic mixture.”

“Tautomers” refer to compounds that are interchangeable forms of a particular compound structure, and that vary in the displacement of hydrogen atoms and electrons. Thus, two structures may be in equilibrium through the movement of π electrons and an atom (usually H). For example, enols and ketones are tautomers because they are rapidly interconverted by treatment with either acid or base. Another example of tautomerism is the aci- and nitro-forms of phenyl nitromethane, that are likewise formed by treatment with acid or base.

Tautomeric forms may be relevant to the attainment of the optimal chemical reactivity and biological activity of a compound of interest.

Compounds of the invention may also exist as “rotamers,” that is, conformational isomers that occur when the rotation leading to different conformations is hindered, resulting a rotational energy barrier to be overcome to convert from one conformational isomer to another.

The compounds of this invention may possess one or more asymmetric centers; such compounds can therefore be produced as individual (R)- or (S)-stereoisomers or as mixtures thereof.

Unless indicated otherwise, the description or naming of a particular compound in the specification and claims is intended to include both individual enantiomers and mixtures, racemic or otherwise, thereof. The methods for the determination of stereochemistry and the separation of stereoisomers are well-known in the art.

The present invention is directed to compounds of Formula I:

wherein

ring A is phenyl, naphthalenyl, pyridyl, quinolinyl, isoquinolinyl, imidazopyridyl, furanyl, thiazolyl, isoxazolyl, pyrazolyl, imidazothiazolyl, benzimidazolyl, or indazolyl;

R₁ is H, alkyl, alkoxy, hydroxyalkylene, OH, halo, phenyl, triazolyl, oxazolyl, isoxazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, piperazinyl, pyrazolyl, oxadiazolyl, pyrrolidinyl, thiophenyl, morpholinyl, or dialkylamino;

R₂ is H, alkyl, alkoxy, hydroxyalkylene, or halo;

Z is NH, N-alkyl, or O;

R₅ is pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, quinazolinyl, quinoxalinyl, pyrazolyl, benzoxazolyl, imidazopyrazinyl, or triazolopyrazinyl, optionally substituted with a one or two substituents independently selected from the group consisting of alkyl, alkoxy, or halo; and

n is 0 or 1.

Enantiomers and diastereomers of the compounds of Formula I are also within the scope of the invention. Also within the scope of the invention are the pharmaceutically acceptable salts of the compounds of Formula I, as well as the pharmaceutically acceptable salts of the enantiomers and diastereomers of the compounds of Formula I.

In preferred embodiments of the invention, Z is NH. In other embodiments, Z is N-alkyl, preferably N—C₁₋₆alkyl, with N—CH₃ being particularly preferred.

In alternative embodiments, N is O.

In preferred embodiments of the invention, ring A is a heteroaryl ring. Preferably, ring A is furanyl, which can be attached to the compounds of Formula I through any available atom, preferably the 2-position carbon atom. In other embodiments, ring A is thiazolyl, which can be attached to the compounds of Formula I through any available atom, preferably the 4-position carbon atom.

In still other embodiments, ring A is isoxazolyl, which can be attached to the compounds of Formula I through any available atom, preferably the 4-position carbon atom.

In yet other embodiments, ring A is pyrazolyl, which can be attached to the compounds of Formula I through any through any available atom, preferably the 3- or 4-position carbon atoms.

Also preferred are embodiments wherein ring A is imidazothiazolyl, which can be attached to the compounds of Formula I through any available atom, preferably the 5-position carbon atom.

In certain embodiments of the invention, ring A is benzimidazolyl, which can be attached to the compounds of Formula I through any available atom, preferably the 2-position carbon atom.

In other embodiments of the invention, ring A is indazolyl, which can be attached to the compounds of Formula I through any available atom, preferably the 3-position carbon atom.

In yet other embodiments, ring A is imidazopyridyl, which can be attached to the compounds of Formula I through any available atom, preferably the 4-, or 7-position carbon atom

In still other embodiments, ring A is quinolinyl, which can be attached to the compounds of Formula I through any available carbon atom, preferably the 5- or 8-position carbon atom.

In other embodiments, ring A is isoquinolinyl, which can be attached to the compounds of Formula I through any available carbon atom, preferably the 4-position carbon atom.

In certain embodiments, ring A is pyridyl, which can be attached to the compounds of Formula I through any available carbon atom, preferably the 2-, 3-, or 4-position carbon atom.

In some embodiments, ring A can be an aryl ring. In certain embodiments, ring A is phenyl. In other embodiments, ring A is naphthalenyl, which can be attached to the compounds of Formula I through any available carbon atom, preferably the 1-position carbon atom.

In preferred embodiments of the invention, R₁ is H. In other embodiments, R₁ is alkyl, preferably a C₁₋₆alkyl, for example, methyl.

In still other embodiments, R₁ is alkoxy, preferably a C₁₋₆alkoxy such as methoxy or ethoxy. Alternatively, R₁ is a substituted alkoxy, preferably substituted with one or more halo such as F, Cl, or Br. One preferred haloalkoxy is difluoromethoxy.

In other embodiments, R₁ is hydroxalkylene, for example, hydroxyC₁₋₆alkylene such as —CH₂—OH or —CH₂CH₂—OH. In yet other embodiments, R₁ is OH.

In other preferred embodiments, R₁ is halo, that is, any one of F, Cl, Br, or I, with F, Cl, or Br being particularly preferred.

In still other embodiments, R₁ is phenyl. In some embodiments, the phenyl can be substituted with at least one halo, for example, phenyl substituted with at least one of F, Cl, or Br.

In certain embodiments, R₁ is triazolyl, with 1,2,3-triazolyl being preferred. The triazolyl can be attached through any available atom. In preferred embodiments, the 1,2,3-triazolyl is attached through the 2-position nitrogen atom. In other embodiments, the 1,2,3-triazolyl is attached through the 1-position nitrogen atom.

In yet other embodiments, R₁ is oxazolyl, which can be attached through any available atom, preferably attached through the 2-position carbon. In some embodiments, the oxazolyl can be substituted with alkyl, for example, a C₁₋₆alkyl such as methyl.

In other embodiments, R₁ is isoxazolyl, which can be attached through any available atom. In some embodiments, the isoxazolyl can be substituted with alkyl, for example, a C₁₋₆alkyl such as methyl.

In still other embodiments, R₁ is pyridyl, which can be attached through any available carbon atom. In some embodiments, the pyridyl can be substituted with at least one alkyl, for example, C₁₋₆alkyl such as methyl.

In certain embodiments, R₁ is pyrimidinyl, which can be attached through any available carbon atom. In other embodiments, R₁ is pyrazinyl, which can be attached through any available carbon atom. In yet other embodiments, R₁ is pyridazinyl, which can be attached through any available carbon atom.

In other embodiments, R₁ is piperazinyl which can be attached through any available atom. In some embodiments, one or both nitrogen atoms of the piperazinyl may be substituted with H or alkyl, for example, C₁₋₆alkyl such as methyl.

In still other embodiments, R₁ is morpholinyl, which can be attached through any available atom. In some embodiments, the nitrogen of the morpholinyl may be substituted with H or alkyl, for example, C₁₋₆alkyl such as methyl.

In yet other embodiments, R₁ is pyrrolidinyl, which can be attached through any available atom. In some embodiments, the nitrogen of the pyrrolidinyl may be substituted with H or alkyl, for example, C₁₋₆alkyl such as methyl.

In other embodiments, R₁ is dialkylamino, for example, dimethylamino, diethylamino, or methylethylamino.

In other embodiments, R₁ is pyrazolyl, which can be attached through any available atom. In some embodiments, the pyrazolyl can be substituted with one or two alkyl, for example, C₁₋₆alkyl such as methyl.

In yet other embodiments, R₁ is oxadiazolyl, which can be a 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, or 1,3,4-oxadiazolyl. Preferably, the oxadiazolyl is 1,2,4-oxadiazolyl. The oxadiazolyl can be attached through any available atom. In some embodiments, the oxadiazolyl can be substituted with alkyl, for example, C₁₋₆alkyl such as methyl.

In still other embodiments, R₁ is thiophenyl, which can be attached through any available carbon atom.

In preferred embodiments of the invention, R₂ is H. In other embodiments, R₂ is alkyl, for example, C₁₋₆alkyl such as methyl or ethyl. In yet other embodiments, R₂ is alkoxy, for example, C₁₋₆alkoxy such as methoxy or ethoxy. In other embodiments, R₂ is hydroxylalkene, for example, —CH₂—OH or CH₂CH₂—OH. In still other embodiments, R₂ is halo, preferably, any one of F, Cl, or Br.

In exemplary embodiments of the invention, ring A is

wherein

-   -   X is CR₆, N, or NR₆;     -   Y is CR₇, N, or NR₇;     -   R₆ is H, alkyl, alkoxy, OH, halo, triazolyl, oxazolyl,         oxadiazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl,         pyrazolyl, or thiophenyl;     -   R₇ is H, alkyl, alkoxy, or halo;     -   R₃ is H, alkyl, alkoxy, hydroxyalkylene, OH, halo, phenyl,         triazolyl, oxazolyl, isoxazolyl, pyridyl, pyrimidinyl,         pyrazinyl, pyridazinyl, piperazinyl, pyrazolyl, oxadiazolyl,         pyrrolidinyl, thiophenyl, morpholinyl, or dialkylamino;     -   R₄ is H, alkyl, alkoxy, or halo;     -   or         -   R₆ and R₇, together with the atoms to which they are             attached, form a 5- or 6-membered heteroaryl ring optionally             substituted with alkyl; or         -   R₃ and R₄, together with the atoms to which they are             attached, form a 6-membered aryl or 6-membered heteroaryl             ring; or         -   R₇ and R₄, together with the atoms to which they are             attached, form a 6-membered aryl or 6-membered heteroaryl             ring.

In certain of these embodiments, X is CR₆ and Y is CR₇.

In other of these embodiments, X is CR₆ and Y is N.

In still other of these embodiments, X is N and Y is CR₇.

In those embodiments wherein X is CR₆, for example those embodiments wherein X is CR₆ and Y is CR₇ or X is CR₆ and Y is N, R₆ is H. Alternatively, R₆ is alkyl, for example, C₁₋₆alkyl such as methyl or ethyl.

In other of these embodiments, R₆ is alkoxy, for example, C₁₋₆alkoxy such as methoxy or ethoxy.

In still other of these embodiments, R₆ is OH.

In yet other of these embodiments, R₆ is halo, preferably, any one of F, Cl, or Br.

In those embodiments wherein X is CR₆, for example those embodiments wherein X is CR₆ and Y is CR₇ or X is CR₆ and Y is N, R₆ is triazolyl with 1,2,3-triazolyl being preferred. The triazolyl can be attached through any available atom. In preferred embodiments, the 1,2,3-triazolyl is attached through the 2-position nitrogen atom. In other embodiments, the 1,2,3-triazolyl is attached through the 1-position nitrogen atom.

In those embodiments wherein X is CR₆, for example those embodiments wherein X is CR₆ and Y is CR₇ or X is CR₆ and Y is N, R₆ is oxazolyl, which can be attached through any available atom. In some embodiments, the oxazolyl can be substituted with alkyl, for example, C₁₋₆alkyl such as methyl.

In those embodiments wherein X is CR₆, for example those embodiments wherein X is CR₆ and Y is CR₇ or X is CR₆ and Y is N, R₆ is oxadiazolyl, which can be a 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, or 1,3,4-oxadiazolyl. Preferably, the oxadiazolyl is 1,2,4-oxadiazolyl. The oxadiazolyl can be attached through any available atom. In some embodiments, the oxadiazolyl can be substituted with alkyl, for example, C₁₋₆alkyl such as methyl.

In those embodiments wherein X is CR₆, for example those embodiments wherein X is CR₆ and Y is CR₇ or X is CR₆ and Y is N, R₆ is pyrazolyl, which can be attached through any available atom. In some embodiments, the pyrazolyl can be substituted with one or two alkyl, for example, C₁₋₆alkyl such as methyl.

In those embodiments wherein X is CR₆, for example those embodiments wherein X is CR₆ and Y is CR₇ or X is CR₆ and Y is N, R₆ is thiophenyl, which can be attached through any available atom.

In those embodiments wherein X is CR₆, for example those embodiments wherein X is CR₆ and Y is CR₇ or X is CR₆ and Y is N, R₆ is pyridyl, which can be attached through any available atom. In some embodiments, the pyridyl can be substituted with one or more alkyl, for example, C₁₋₆alkyl such as methyl. One exemplary substituted pyridyl is methyl-pyridyl.

In those embodiments wherein X is CR₆, for example those embodiments wherein X is CR₆ and Y is CR₇ or X is CR₆ and Y is N, R₆ is pyrimidinyl, which can be attached through any available atom. In other embodiments, R₆ is pyrazinyl, which can be attached through any available atom. In still other embodiments, R₆ is pyridazinyl, which can be attached through any available atom.

In preferred embodiments wherein Y is CR₇, for example, those embodiments wherein X is CR₆ and Y is CR₇ or X is N and Y is CR₇, R₇ is H. In other embodiments, R₇ is alkyl, for example, C₁₋₆alkyl such as methyl or ethyl.

In those embodiments wherein Y is CR₇, for example, those embodiments wherein X is CR₆ and Y is CR₇ or X is N and Y is CR₇, R₇ is alkoxy, for example, C₁₋₆alkoxy such as methoxy or ethoxy. In other embodiments, the alkoxy is substituted with, for example, one or more halo. One preferred substituted alkoxy is difluoromethoxy.

In those embodiments wherein Y is CR₇, for example, those embodiments wherein X is CR₆ and Y is CR₇ or X is N and Y is CR₇, R₇ is halo, preferably one of F, Cl, or Br.

In some embodiments, X is NR₆ and Y is CR₇.

In other embodiments, X is CR₆ and Y is NR₇.

In those embodiments wherein X is NR₆ and Y is CR₇ or X is CR₆ and Y is NR₇, R₆ and R₇, together with the atoms to which they are attached, form a 5-membered heteroaryl ring. These 5-membered rings can be optionally substituted with alkyl, for example C₁₋₆alkyl such as methyl.

In those embodiments wherein X is NR₆ and Y is CR₇ or X is CR₆ and Y is NR₇, R₆ and R₇, together with the atoms to which they are attached, form a 6-membered heteroaryl ring. These 5-membered rings can be optionally substituted with alkyl, for example C₁₋₆alkyl such as methyl.

In those embodiments wherein Y is CR₇ or NR₇, R₇ and R₄, together with the atoms to which they are attached, form a 6-membered aryl ring. Alternatively, R₇ and R₄, together with the atoms to which they are attached, form a 6-membered heteroaryl ring.

In preferred embodiments, R₃ is H. In other embodiments, R₃ is alkyl, for example, C₁₋₆alkyl such as methyl or ethyl.

In other embodiments, R₃ is alkoxy, for example, C₁₋₆alkoxy such as methoxy or ethoxy. In some embodiments, the alkoxy is substituted with, for example, one or more halo. One preferred substituted alkoxy is difluoromethoxy.

In some embodiments, R₃ is hydroxyalkylene, for example, hydroxyC₁₋₆alklene such as —CH₂—OH and —CH₂CH₂—OH. In yet other embodiments, R₃ is OH.

In other preferred embodiments, R₃ is halo, preferably any one of F, Cl, or Br.

In still other embodiments, R₃ is phenyl. In some embodiments, the phenyl can be substituted with one or more halo, for example, phenyl substituted with at least one of F, Cl, or Br.

In certain embodiments, R₃ is triazolyl, with 1,2,3-triazolyl being preferred. The triazolyl can be attached through any available atom. In preferred embodiments, the 1,2,3-triazolyl is attached through the 2-position nitrogen atom. In other embodiments, the 1,2,3-triazolyl is attached through the 1-position nitrogen atom.

In yet other embodiments, R₃ is oxazolyl, which can be attached through any available atom, preferably attached through the 2-position carbon. In some embodiments, the oxazolyl can be substituted with alkyl, for example, a C₁₋₆alkyl such as methyl.

In other embodiments, R₃ is isoxazolyl, which can be attached through any available atom. In some embodiments, the isoxazolyl can be substituted with alkyl, for example, a C₁₋₆alkyl such as methyl.

In other embodiments, R₃ is oxadiazolyl, which can be a 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, or 1,3,4-oxadiazolyl. Preferably, the oxadiazolyl is 1,2,4-oxadiazolyl. The oxadiazolyl can be attached through any available atom. In some embodiments, the oxadiazolyl can be substituted with alkyl, for example, C₁₋₆alkyl such as methyl.

In still other embodiments, R₃ is pyridyl, which can be attached through any available carbon atom. In some embodiments, the pyridyl can be substituted with one or more alkyl, for example, C₁₋₆alkyl such as methyl.

In other embodiments, R₃ is pyrazolyl, which can be attached through any available atom. In some embodiments, the pyrazolyl can be substituted with one or two alkyl, for example, C₁₋₆alkyl such as methyl.

In certain embodiments, R₃ is pyrimidinyl, which can be attached through any available carbon atom. In other embodiments, R₃ is pyrazinyl, which can be attached through any available carbon atom. In yet other embodiments, R₃ is pyridazinyl, which can be attached through any available carbon atom.

In other embodiments, R₃ is piperazinyl which can be attached through any available atom. In some embodiments, one or both nitrogen atoms of the piperazinyl may be substituted with H or alkyl, for example, C₁₋₆alkyl such as methyl.

In still other embodiments, R₃ is morpholinyl, which can be attached through any available atom. In some embodiments, the nitrogen atom of the morpholinyl may be substituted with H or alkyl, for example, C₁₋₆alkyl such as methyl.

In yet other embodiments, R₃ is pyrrolidinyl, which can be attached through any available atom. In some embodiments, the nitrogen atom of the pyrrolidinyl may be substituted with H or alkyl, for example, C₁₋₆alkyl such as methyl.

In other embodiments, R₃ is dialkylamino, for example, dimethylamino, diethylamino, or methylethylamino.

In other embodiments, R₃ is pyrazolyl, which can be attached through any available atom. In some embodiments, the pyrazolyl can be substituted with one or two alkyl, for example, C₁₋₆alkyl such as methyl.

In still other embodiments, R₃ is thiophenyl, which can be attached through any available carbon atom.

In preferred embodiments of the invention, R₄ is H. In other embodiments, R₄ is alkyl, for example, C₁₋₆alkyl such as methyl or ethyl. In still other embodiments, R₄ is alkoxy, for example, C₁₋₆alkoxy such as methoxy or ethoxy. In yet other embodiments, R₄ is halo, preferably, any one of F, Cl, or Br.

In some embodiments, R₃ and R₄, together with the atoms to which they are attached, form a 6-membered aryl ring.

In other embodiments, R₃ and R₄, together with the atoms to which they are attached, form a 6-membered heteroarylaryl ring.

In preferred embodiments of the invention, R₅ is a heteroaryl ring. According to some embodiments of the invention, R₅ is pyridyl, which can be attached through any available atom, optionally substituted with a one or two substituents independently selected from the group consisting of alkyl, alkoxy, or halo. In some embodiments, alkyl is trihaloalkyl, for example trifluoromethyl.

According to some embodiments of the invention, R₅ is pyrimidinyl, which can be attached through any available atom, optionally substituted with a one or two substituents independently selected from the group consisting of alkyl, alkoxy, or halo. In some embodiments, alkyl is trihaloalkyl, for example trifluoromethyl.

According to some embodiments of the invention, R₅ is pyrazinyl, which can be attached through any available atom, optionally substituted with a one or two substituents independently selected from the group consisting of alkyl, alkoxy, or halo. In some embodiments, alkyl is trihaloalkyl, for example trifluoromethyl.

According to some embodiments of the invention, R₅ is pyridazinyl, which can be attached through any available atom, optionally substituted with a one or two substituents independently selected from the group consisting of alkyl, alkoxy, or halo. In some embodiments, alkyl is trihaloalkyl, for example trifluoromethyl.

According to some embodiments of the invention, R₅ is quinazolinyl, which can be attached through any available atom, optionally substituted with a one or two substituents independently selected from the group consisting of alkyl, alkoxy, or halo. In some embodiments, alkyl is trihaloalkyl, for example trifluoromethyl.

According to some embodiments of the invention, R₅ is quinoxalinyl, which can be attached through any available atom, optionally substituted with a one or two substituents independently selected from the group consisting of alkyl, alkoxy, or halo. In some embodiments, alkyl is trihaloalkyl, for example trifluoromethyl.

According to some embodiments of the invention, R₅ is pyrazolyl, which can be attached through any available atom, optionally substituted with a one or two substituents independently selected from the group consisting of alkyl, alkoxy, or halo. In some embodiments, alkyl is trihaloalkyl, for example trifluoromethyl. In some embodiments, the pyrazolyl is methyl-pyrazolyl substituted with trifluoromethyl.

According to some embodiments of the invention, R₅ is benzoxazolyl, which can be attached through any available atom, optionally substituted with a one or two substituents independently selected from the group consisting of alkyl, alkoxy, or halo. In some embodiments, alkyl is trihaloalkyl, for example trifluoromethyl.

According to some embodiments of the invention, R₅ is imidazopyrazinyl, which can be attached through any available atom, optionally substituted with a one or two substituents independently selected from the group consisting of alkyl, alkoxy, or halo. In some embodiments, alkyl is trihaloalkyl, for example trifluoromethyl.

According to some embodiments of the invention, R₅ is triazolopyrazinyl, which can be attached through any available atom, optionally substituted with a one or two substituents independently selected from the group consisting of alkyl, alkoxy, or halo. In some embodiments, alkyl is trihaloalkyl, for example trifluoromethyl.

In some embodiments of the invention n is 0. In other embodiments, n is 1.

The invention relates to methods of using the compounds described herein to treat subjects diagnosed with or suffering from a disease, disorder, or condition mediated by orexin receptor activity. These methods are accomplished by administering to the subject a compound of the invention.

Diseases, disorders, and conditions mediated by orexin receptor activity include disorders of the sleep-wake cycle, insomnia, restless legs syndrome, jet-lag, disturbed sleep, sleep disorders secondary to neurological disorders, mania, depression, manic depression, schizophrenia, pain syndromes, fibromyalgia, neuropathic pain, catatonia, Parkinson's disease, Tourette's syndrome, anxiety, delirium, dementia, overweight, obesity, or conditions related to overweight or obesity, insulin resistance, type II diabetes, hyperlipidemia, gallstones, angina, hypertension, breathlessness, tachycardia, infertility, sleep apnea, back and joint pain, varicose veins, osteoarthritis, hypertension, tachycardia, arrhythmias, angina pectoris, acute heart failure, ulcers, irritable bowel syndrome, diarrhea gastroesophageal reflux, mood disorders, post-traumatic stress disorder, panic disorders, attention deficit disorders, cognitive deficiencies, or substance abuse.

Compounds of the invention are particularly suited for the treatment of mood disorders, post-traumatic stress disorder, panic disorders, attention deficit disorders, cognitive deficiencies, or substance abuse.

Sleep disorders include, but are not limited to, sleep-wake transition disorders, insomnia, restless legs syndrome, jet-lag, disturbed sleep, and sleep disorders secondary to neurological disorders (e.g., manias, depressions, manic depression, schizophrenia, and pain syndromes (e.g., fibromyalgia, neuropathic).

Metabolic disorders include, but are not limited to, overweight or obesity and conditions related to overweight or obesity, such as insulin resistance, type II diabetes, hyperlipidemia, gallstones, angina, hypertension, breathlessness, tachycardia, infertility, sleep apnea, back and joint pain, varicose veins and osteoarthritis.

Neurological disorders include, but are not limited to, Parkinson's disease, Alzheimer's disease, Tourette's Syndrome, catatonia, anxiety, delirium and dementias.

In treatment methods according to the invention, an effective amount of a pharmaceutical agent according to the invention is administered to a subject suffering from or diagnosed as having such a disease, disorder, or condition. An “effective amount” means an amount or dose sufficient to generally bring about the desired therapeutic or prophylactic benefit in patients in need of such treatment for the designated disease, disorder, or condition. Effective amounts or doses of the compounds of the present invention may be ascertained by routine methods such as modeling, dose escalation studies or clinical trials, and by taking into consideration routine factors, e.g., the mode or route of administration or drug delivery, the pharmacokinetics of the compound, the severity and course of the disease, disorder, or condition, the subject's previous or ongoing therapy, the subject's health status and response to drugs, and the judgment of the treating physician. An example of a dose is in the range of from about 0.001 to about 200 mg of compound per kg of subject's body weight per day, preferably about 0.05 to 100 mg/kg/day, or about 1 to 35 mg/kg/day, in single or divided dosage units (e.g., BID, TID, QID). For a 70-kg human, an illustrative range for a suitable dosage amount is from about 0.05 to about 7 g/day, or about 0.2 to about 2.5 g/day.

Once improvement of the patient's disease, disorder, or condition has occurred, the dose may be adjusted for preventative or maintenance treatment. For example, the dosage or the frequency of administration, or both, may be reduced as a function of the symptoms, to a level at which the desired therapeutic or prophylactic effect is maintained. Of course, if symptoms have been alleviated to an appropriate level, treatment may cease. Patients may, however, require intermittent treatment on a long-term basis upon any recurrence of symptoms.

In addition, the compounds of the invention may be used in combination with additional active ingredients in the treatment of the above conditions. The additional active ingredients may be coadministered separately with a compound of the invention or included with such an agent in a pharmaceutical composition according to the invention. In an exemplary embodiment, additional active ingredients are those that are known or discovered to be effective in the treatment of conditions, disorders, or diseases mediated by orexin activity, such as another orexin modulator or a compound active against another target associated with the particular condition, disorder, or disease. The combination may serve to increase efficacy (e.g., by including in the combination a compound potentiating the potency or effectiveness of an active agent according to the invention), decrease one or more side effects, or decrease the required dose of the active agent according to the invention.

The compounds of the invention are used, alone or in combination with one or more additional active ingredients, to formulate pharmaceutical compositions of the invention. A pharmaceutical composition of the invention comprises: (a) an effective amount of at least one compound in accordance with the invention; and (b) a pharmaceutically acceptable excipient.

Delivery forms of the pharmaceutical compositions containing one or more dosage units of the active agents may be prepared using suitable pharmaceutical excipients and compounding techniques known or that become available to those skilled in the art. The compositions may be administered in the inventive methods by a suitable route of delivery, e.g., oral, parenteral, rectal, topical, or ocular routes, or by inhalation.

The preparation may be in the form of tablets, capsules, sachets, dragees, powders, granules, lozenges, powders for reconstitution, liquid preparations, or suppositories. Preferably, the compositions are formulated for intravenous infusion, topical administration, or oral administration.

For oral administration, the compounds of the invention can be provided in the form of tablets or capsules, or as a solution, emulsion, or suspension. To prepare the oral compositions, the compounds may be formulated to yield a dosage of, e.g., from about 0.05 to about 100 mg/kg daily, or from about 0.05 to about 35 mg/kg daily, or from about 0.1 to about 10 mg/kg daily. For example, a total daily dosage of about 5 mg to 5 g daily may be accomplished by dosing once, twice, three, or four times per day.

Oral tablets may include a compound according to the invention mixed with pharmaceutically acceptable excipients such as inert diluents, disintegrating agents, binding agents, lubricating agents, sweetening agents, flavoring agents, coloring agents and preservative agents. Suitable inert fillers include sodium and calcium carbonate, sodium and calcium phosphate, lactose, starch, sugar, glucose, methyl cellulose, magnesium stearate, mannitol, sorbitol, and the like. Exemplary liquid oral excipients include ethanol, glycerol, water, and the like. Starch, polyvinyl-pyrrolidone (PVP), sodium starch glycolate, microcrystalline cellulose, and alginic acid are suitable disintegrating agents. Binding agents may include starch and gelatin. The lubricating agent, if present, may be magnesium stearate, stearic acid or talc. If desired, the tablets may be coated with a material such as glyceryl monostearate or glyceryl distearate to delay absorption in the gastrointestinal tract, or may be coated with an enteric coating.

Capsules for oral administration include hard and soft gelatin capsules. To prepare hard gelatin capsules, compounds of the invention may be mixed with a solid, semi-solid, or liquid diluent. Soft gelatin capsules may be prepared by mixing the compound of the invention with water, an oil such as peanut oil or olive oil, liquid paraffin, a mixture of mono and di-glycerides of short chain fatty acids, polyethylene glycol 400, or propylene glycol.

Liquids for oral administration may be in the form of suspensions, solutions, emulsions or syrups or may be lyophilized or presented as a dry product for reconstitution with water or other suitable vehicle before use. Such liquid compositions may optionally contain: pharmaceutically-acceptable excipients such as suspending agents (for example, sorbitol, methyl cellulose, sodium alginate, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminum stearate gel and the like); non-aqueous vehicles, e.g., oil (for example, almond oil or fractionated coconut oil), propylene glycol, ethyl alcohol, or water; preservatives (for example, methyl or propyl p-hydroxybenzoate or sorbic acid); wetting agents such as lecithin; and, if desired, flavoring or coloring agents.

The active agents of this invention may also be administered by non-oral routes. For example, the compositions may be formulated for rectal administration as a suppository. For parenteral use, including intravenous, intramuscular, intraperitoneal, or subcutaneous routes, the compounds of the invention may be provided in sterile aqueous solutions or suspensions, buffered to an appropriate pH and isotonicity or in parenterally acceptable oil. Suitable aqueous vehicles include Ringer's solution and isotonic sodium chloride. Such forms will be presented in unit-dose form such as ampules or disposable injection devices, in multi-dose forms such as vials from which the appropriate dose may be withdrawn, or in a solid form or pre-concentrate that can be used to prepare an injectable formulation. Illustrative infusion doses may range from about 1 to 1000 μg/kg/minute of compound, admixed with a pharmaceutical carrier over a period ranging from several minutes to several days.

For topical administration, the compounds may be mixed with a pharmaceutical carrier at a concentration of about 0.1% to about 10% of drug to vehicle. Another mode of administering the compounds of the invention may utilize a patch formulation to affect transdermal delivery.

Compounds of the invention may alternatively be administered in methods of this invention by inhalation, via the nasal or oral routes, e.g., in a spray formulation also containing a suitable carrier.

Exemplary compounds useful in methods of the invention will now be described by reference to the illustrative synthetic schemes for their general preparation below and the specific examples that follow. Artisans will recognize that, to obtain the various compounds herein, starting materials may be suitably selected so that the ultimately desired substituents will be carried through the reaction scheme with or without protection as appropriate to yield the desired product. Alternatively, it may be necessary or desirable to employ, in the place of the ultimately desired substituent, a suitable group that may be carried through the reaction scheme and replaced as appropriate with the desired substituent. Unless otherwise specified, the variables are as defined above in reference to Formula (I). Reactions may be performed between the melting point and the reflux temperature of the solvent, and preferably between 0° C. and the reflux temperature of the solvent. Reactions may be heated employing conventional heating or microwave heating. Reactions may also be conducted in sealed pressure vessels above the normal reflux temperature of the solvent.

Intermediate compounds of formula (IIIa) and (IIIb) can be prepared as outlined in Scheme 1 from commercially available or synthetically accessible compounds of formula (A) where R₃, R₄, X and Y are defined in formula (I) as above. Compounds of formula (IIa) and (IIb), are obtained by reacting a compound of formula (A), with commercially available 1,2,3-triazole, in the presence K₂CO₃ in DMF or dioxane, at temperatures ranging from about 60° C. to about 100° C. Compounds of formula (IIIa) and (IIIb) are obtained by reacting compounds of formula (II) in the presence of a base such as NaOH in a solvent such as EtOH at temperatures ranging from 80° C. to 100° C. One skilled in the art will recognize that 1,2,3-triazole can exist in two tautomeric forms defined as 2H-[1,2,3]triazole and 1H-[1,2,3]triazole thus accounting for the formation of (IIIa) and (IIIb).

Intermediate compounds of formula (III) can be prepared as outlined in Scheme 2 from commercially available or synthetically accessible compounds of formula (IVa-c). Compounds of formula (III), (Va) and (Vb) are obtained by reacting compounds of formula (IVa), (IVb) and (IVc) where Hal is —Br, or —I; W is CO₂H, CO₂Alkyl, or CN and R₃ and R₄ are —H, halo, —C₁₋₄alkyl, —C₁₋₄alkoxy and R₃ and R₄ together with the atoms to which they are attached form a 6-membered aryl or 6 membered heteroaryl ring, with commercially available 1,2,3-triazole, in the presence of, for example, copper(I)iodide, Cs₂CO₃ and trans-N,N′-dimethyl-1,2-cyclohexanediamine in, for example, DMF or dioxane, at temperatures ranging from about 60° C. to about 120° C. Compounds of formula (IVc) can be converted to the corresponding esters (Vb) by treatment with, for example, alkyl iodide in the presence of a base such as K₂CO₃ in a solvent such as DMF. Compounds of formula (III) are obtained by reacting a compound of formula (Va) and (Vb) in the presence of a base such as NaOH in a solvent such as EtOH at temperatures ranging from about 80° C. to about 100° C. One skilled in the art will recognize that 1,2,3-triazole can exist in two tautomeric forms defined as 2H-[1,2,3]triazole and 1H-[1,2,3]triazole thus compounds of formula (Va), (Vb), and (III) can also exist as the N1 linked variant (structure not shown).

Intermediate compounds of formula (IX) are prepared as outlined in Scheme 3 from commercially available or synthetically accessible compounds of formula (VI) where R₃, R₄, X, and Y are defined as in formula I above, G is SnBu₃ or 4,4,5,5 tetramethyl-1,dioxaboralane and D is Cl, or Br, preferably Br in this case. Compounds of formula (VIII) are obtained by reacting a compound of formula (VI) with commercially available (VII) in the presence of a catalyst such as 1,1′-bis(di-tert-butylphosphino)ferrocene palladium dichloride and a base such as Na₂CO₃ in a solvent such as 2-MeTHF or THF at temperatures ranging from about 60° C. to about 90° C. Compounds of formula (IX) are obtained by reacting a compound of formula (VIII) in the presence of a base such as NaOH in a solvent such as MeOH at temperatures ranging from about 80° C. to about 100° C. or acids such as H₂SO₄ in solvents such as H₂O at temperatures ranging from about 80 to about 100° C.

Intermediate compound (XIV) is prepared as outlined in Scheme 4 from commercially available compound (X). Compounds (XI) are obtained by reacting compound (X) with commercially available acrolein in a solvent such as 1,4 dioxane at temperatures of about 200° C. in a microwave reactor. Compound (XII) can be prepared from compound (XI) by treatment with an acid such as HBr in a solvent such as toluene at a temperature of about 90° C. Compound (XIII) can be obtained by treatment of compound (XII) with commercially available iodoethane and a base such as K₂CO₃ in a solvent such as DMF at temperatures ranging from about 45° C. to about 65° C. Compound (XIV) is obtained by treating compound (XIII) with a base such as NaOH in a solvent such as MeOH at temperatures ranging from about 80° C. to about 100° C.

Intermediate compounds of formula (XVI) are prepared as outlined in Scheme 5 from commercially available or synthetically accessible compounds of formula (XIV) where R² is —H, —C₁₋₄alkyl, or —C₁₋₄alkoxy and D is Cl, or Br. Compounds of formula (XV) are obtained by reacting a compound of formula (XIV) with commercially available (VII) in the presence of a catalyst such as Pd(dppf)Cl₂ and a base such as Na₂CO₃ in a solvent such as 2-MeTHF at temperatures ranging from 75° C. to 150° C. Compounds of formula (XVI) are obtained by reacting a compound of formula (XV) in the presence of a base such as NaOH in a solvent such as MeOH at temperatures ranging from about 80° C. to about 100° C.

Intermediate compounds of formula (XXI) can be prepared as outlined in Scheme 6 from commercially available or synthetically accessible compounds of formula (XVII) where Hal is Br or I; and where R₃ and R₄ are —H, halo, alkyl, alkoxy. Compounds of formula (XVIIIa) can be converted to the corresponding ester (XVIIIb) by treatment with thionyl chloride in a solvent such as MeOH. Compounds of the formula (XX) are obtained by reacting compounds of formula (XVIIIb) with commercially available compounds of the formula XIX where L is a heterocycle such as pyrazolyl, pyridyl, or oxazolyl; G is SnBu₃ or 4,4,5,5 tetramethyl-1,dioxaboralane and R₁ and R₂ are —H, -alkyl, or -alkoxy in the presence of a catalyst such as Pd(Ph₃P)₄ and a base such as Na₂CO₃ in a mixture of solvents such as DME and H₂O at temperatures ranging from 100° C. to 150° C. Compounds of formula (XXI) are obtained by reacting a compound of formula (XX) in the presence of a base such as NaOH in a solvent such as MeOH at temperatures ranging from about 80° C. to about 100° C.

Intermediate compounds of formula (XXIV) and (XXVII) are readily prepared as outlined in Scheme 7 from commercially available or synthetically accessible compounds of formula (XXII) or (XXV). Compounds of formula (XXIII) can be obtained from compounds of formula (XXII) as described in the references listed in Scheme 7. Compounds of formula (XXIV) can be obtained from compounds of formula (XXIII) by treatment with reducing agents such as Dibal-H, LiAlH₄ or LiBH₄ in solvents such as THF or diethyl ether at temperatures ranging from about 0° C. to about 70° C. Compounds of formula (XXVI) can be obtained from compounds of formula (XXIII) by treatment with bases such as aqueous sodium hydroxide, potassium hydroxide and lithium hydroxide in solvents such as water, methanol or THF. Compounds of formula (XXVI) can also be obtained from compounds of formula (XXV) using procedures described in WO 2004074292.

Referring to Scheme 8, where PG₁ is a Boc protecting group, compounds of formula (±)-(XXVII) were resolved into individual enantiomers of formula (+)-(XXVII) and (−)-(XXVII) using SFC chromatography on a chiral SFC (CHIRALPAK IC 5 μM 250×20 mm) column using 80% CO₂/20% iPrOH as the mobile phase.

Referring to Scheme 9, where PG₁ is a Boc protecting group, compounds of formula (XXVIII) are prepared compounds of formula (+)-(XXIX). Compounds of formula (XXVIII) are readily prepared from compounds of formula (+)-(XXVII) by treatment with metal catalyst such as PtO₂, Pd/C, or Pd(OH)₂ in solvents such as AcOH, MeOH or EtOH under an atmosphere of hydrogen. Compounds of formula (XXIX) are readily prepared from compounds of formula (XXVIII) by reaction with DPPA and TEA in a solvent such as toluene at temperatures ranging from about 0° C. to about 100° C., preferably about 65° C. for a period of about 1 to 8 hours. BnOH is then added to afford a compound of formula (XXIX).

According to Scheme 10, compound (XXXI) is obtained by reaction of compound (XXX) with, for example, DPPA and TEA in a solvent such as toluene at temperatures ranging from about 0° C. to about 100° C., preferably about 65° C. for a period of about 1 to 8 hours, preferably about 4 h. BnOH is then added to afford a compound of formula (XXXI). Compound (XXXII) is obtained from compound (XXXI) by reaction with trimethylphenyl ammonium tribromide at temperatures ranging from about 0° C. to about 23° C., preferably about 0° C. for a period of from 2 to 6 hours, preferably about 4 hours. Compound (XXIII) is obtained from compound (XXXII) by treatment with a base, preferably NaH is a solvent such as DMF. Compound (XXXIV) is obtained from compound (XXXIII) by elimination of HBr with tBuOK in a solvent such as THF in the presence for a period ranging from 2 to 24 hours. Compound (XXXV) is obtained from compound (XXXIV) by hydroboration oxidation by treating the compound (XXXIV) with borane in a solvent such as THF at temperatures ranging from about 0° C. to about 23° C., preferably at about 23° C., for 2 to 12 hours, preferably about 2 hours followed by reaction with, for example, hydrogen peroxide in the presence of a base such as sodium hydroxide.

Referring to Scheme 11, one skilled in the art would recognize that compounds of formula (XLI) may be obtained from compounds of formula (XXXVI) by converging pathways. In one sequence, a compound of formula (XXXVII) is obtained by treating a compound of formula (XXXVI) with R⁵Cl, where R⁵ is optionally substituted pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, quinazolinyl, quinoxalinyl, pyrazolyl, benzoxazolyl, imidazopyrazinyl, triazolopyrazinyl. Commercially available or synthetically accessible suitably substituted heteroaryl compounds of formula R⁵Cl are reacted with compounds of formula (XXXVI), in the presence of a suitably selected tertiary organic or inorganic base such as NaH, Cs₂CO₃, K₂CO₃, TEA, iPr₂NEt and the like; in a solvent such as DMF, dichloromethane, THF, and the like; at a temperature between room temperature and the reflux temperature of the solvent. In a preferred embodiment the base is NaH and the solvent is DMF. Removal of the tert-butylcarbamate (Boc) in compounds of formula (XXXVII) is accomplished by using methods known to one skilled in the art, such as, HCl, TFA, or p-toluenesulfonic acid, in a solvent such as CH₃OH, dioxane, or CH₂Cl₂. In a preferred embodiment, a compound of formula (XXXVII) is treated with TFA in DCM or HCl to afford a compound of formula (XXXVIII). A compound of formula (XLI) is obtained by treating a compound of formula (XXXVIII) with (R¹R²A)CO₂H, where R¹ is H, alkyl, alkoxy, hydroxyalkylene, OH, halo, phenyl, triazolyl, oxazolyl, isoxazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, piperazinyl, pyrazolyl, oxadiazolyl, pyrrolidinyl, thiophenyl, morpholinyl, or dialkylamino and R₂ is H, alkyl, alkoxy, or halo. Commercially available or synthetically accessible suitably substituted carboxylic acid compounds of formula (R¹R²A)CO₂H are combined with compounds of formula (XXXVIII) using under amide coupling methods known to one skilled in the art, such as, CDI, EDCI, HATU, or T3P in a solvent such as THF, DCM, or DMF In a preferred embodiment, a compound of formula (XXXVIII) and (R¹R²A)CO₂H are treated with EDCI in the presence of HOBT in DMF at ambient temperature to afford a compound of formula (XLI). One skilled in the art would recognize that compounds of formula (XLI) may also be obtained from compounds of formula (XL). Removal of the tert-butylcarbamate (Boc) in compounds of formula (XXXVI) is accomplished by using methods known to one skilled in the art, such as, HCl, TFA, or p-toluenesulfonic acid, in a solvent such as CH₃OH, dioxane, or CH₂Cl₂. In a preferred embodiment, a compound of formula (XXXVI) is treated with TFA in DCM or HCl to afford a compound of formula (XXXIX). A compound of formula (XL) is obtained by treating a compound of formula (XXXIX) with (R¹R²A)CO₂H. Commercially available or synthetically accessible suitably substituted carboxylic acid compounds of formula (R¹R²A)CO₂H are combined with compounds of formula (XXXIX) using under amide coupling methods known to one skilled in the art, such as, CDI, EDCI, HATU, or T3P in a solvent such as THF, DCM, or DMF In a preferred embodiment, a compound of formula (XXXIX) and (R¹R²A)CO₂H are treated with EDCI in the presence of HOBT in DMF at ambient temperature to afford a compound of formula (XL). A compound of formula (XLI) is obtained by treating a compound of formula (XL) with R⁵Cl. Commercially available or synthetically accessible suitably substituted heteroaryl compounds of formula R⁵Cl are reacted with compounds of formula (XL), in the presence of a suitably selected tertiary organic or inorganic base such as NaH, Cs₂CO₃, K₂CO₃, TEA, iPr₂NEt and the like; in a solvent such as DMF, dichloromethane, THF, and the like; at a temperature between room temperature and the reflux temperature of the solvent. In a preferred embodiment the base is NaH and the solvent is DMF to provide compounds of formula (XLI).

Referring to Scheme 12, compounds of formula (XLVI) were synthesized from compounds of formula (XLII) where PG₁ is Boc, PG₃ is Cbz, Z is O or NH and n is 0 or 1. PG₃ was removed when compound of formula (XLII) was treated with, for example, a Pd catalyst such as 10 wt % Pd/C wet Degussa under an atmosphere of H₂ in a solvent such as EtOH to give compound of formula (XLIII). Compounds of formula (XLIV) were obtained from compounds of formula (XLIII) using compounds of formula (XLVIII) in a suitable solvent such as DMSO or DMF in the presence of a base such as K₂CO₃ at a temperature of about 70° C. Compounds of formula (XLIV) could also be obtained when compounds of formula (XLIII) and (XLVIII) were treated with a Pd catalyst such as Pd(OAc)₂, a ligand such as racemic BINAP, a base such as sodium tert-butoxide in a solvent such as toluene at a temperature of about 70° C. Compound of formula (XLV) were obtained from compounds of formula (XLIV) when treated with an acid such as HCl in a suitable solvent such as EtOAc or DCM at room temperature. Compound of formula (XLVI) were obtained from compounds of formula (XLV) using compounds of formula (XLVII) in a suitable solvent such as DMF or DCM in the presence of a peptide coupling reagent such as HATU or T3P, a base such as DIPEA at a temperature ranging from room temperature to about 45° C.

Referring to Scheme 13, compounds of formula (L) were obtained from compound of formula (XLIX) using compounds of formula (LI) in a solvent such as DME in the presence of a Pd catalyst such as Pd(PPh₃)₄, an additive or catalyst such as copper iodide at a temperature ranging from about 120° C. to about 150° C.

EXAMPLES Abbreviations

Term Acronym Acetic Acid HOAc Acetonitrile ACN Apparent app Aqueous aq Atmosphere atm 2-(1H-9-Azobenzotriazole-1-yl)-1,1,3,3- HATU tetramethylaminium hexafluorophosphate Benzyl Bn 2,2′-bis(diphenylphosphino)-1,1′-binaphthalene BINAP [1,1′-Bis(di-tert- PdCl₂(dtbpf) butylphosphino)ferrocene]dichloropalladium(II) Broad br tert-Butylcarbamoyl Boc/Boc Dichloromethane DCM Diisopropylethylamine DIPEA 1,2-Dimethoxyethane DME N,N-Dimethylformamide DMF Dimethylsulfoxide DMSO Doublet d Electrospray ionization ESI Enantiomeric excess ee Ethanol EtOH Ethyl Acetate EtOAc, or EA Grams g Hertz Hz High-pressure liquid chromatography HPLC Hours h Liquid chromatography and mass spectrometry LCMS Mass spectrometry MS Mass to charge ratio m/z Methanol MeOH Microliter μL Milligrams mg Milliliter mL Millimoles mmol Minute min Molar M Multiplet m Normal N Nuclear magnetic resonance NMR Palladium on carbon Pd/C Palladium hydroxide on carbon Pd(OH)₂/C Parts per million ppm Phenyl Ph Propylphosphonic anhydride T₃P Retention time R_(t) Room temperature rt Quartet q Singlet s Supercritical Fluid Chromatography SFC Temperature T Thin layer chromatography TLC Times X Triethylamine TEA Trifluoroacetic acid TFA Triplet t

Chemistry:

In obtaining the compounds described in the examples below and the corresponding analytical data, the following experimental and analytical protocols were followed unless otherwise indicated.

Unless otherwise stated, reaction mixtures were magnetically stirred at room temperature (rt) under a nitrogen atmosphere. Where solutions were “dried,” they were generally dried over a drying agent such as Na₂SO₄ or MgSO₄, filtered and concentrated. Where mixtures, solutions, and extracts were “concentrated”, they were typically concentrated on a rotary evaporator under reduced pressure. Reactions under microwave irradiation conditions were carried out in a Biotage Initiator or CEM Discover instrument.

Melting point determinations were performed in open capillary tubes on a FP62 or MP50 apparatus (Mettler-Toledo). Melting points were measured with a temperature gradient of 10° C./minute. Maximum temperature was 300° C. The melting point was read from a digital display.

Normal-phase flash column chromatography (FCC) was performed on silica gel (SiO₂) using prepackaged cartridges, eluting with the indicated solvents.

Where compounds were purified by “Prep HPLC” the method employed was either:

Preparative reverse-phase high performance liquid chromatography (HPLC) was performed on a Gilson HPLC with an Xterra Prep RP₁₈ (5 m, 30×100 mm, or 50×150 mm) column, and a gradient of 10 to 99% acetonitrile/water (20 mM NH₄OH) over 12 to 18 min, and a flow rate of 30 mL/min. or

Preparative reverse-phase high performance liquid chromatography (HPLC) was performed on a Agilent 1100 Series HPLC with an XBridge C18 column (5 m, 30×100 mm), mobile phase of 5% ACN in 20 mM NH4OH (hold for 2 min) then ramp 5-99% ACN over 15 min, hold at 99% ACN for 5 min. and a flow rate of 40 mL/min. or

Preparative reverse-phase high performance liquid chromatography (HPLC) was performed on a Agilent 1100 Series HPLC with an XBridge C18 column (5 m, 50×100 mm), mobile phase of 5% ACN in 20 mM NH4OH (hold for 2 min) then ramp 5-99% ACN over 15 min, hold at 99% ACN for 5 min. and a flow rate of 80 mL/min. or

Preparative reverse-phase high performance liquid chromatography (HPLC) was performed on a Gilson HPLC with an Xterra Prep RP₁₈ (5 μm, 30×100 mm, or 50×150 mm) column, and a gradient of 10 to 99% acetonitrile/water (20 mM NH₄OH) over 12 to 18 min, and a flow rate of 30 mL/min.

Analytical chromatography data was acquired using an Agilent 1100 HPLC, with an Inertsil ODS-3 3 mm 4.6×50 mm column, purchased from GL Sciences (Part #1010L050W046). Samples were run using a gradient profile of 10-99% acetonitrile (ACN) in water, each containing 0.05% trifluoroacetic acid (TFA) over 1.6 minutes, then holding at 99% acetonitrile for 0.3 minutes. Flow rate was 5 mL/min and column temperature was set to 50° C. (Method A).

Mass spectra (MS) were obtained on an Agilent series 1100 MSD using electrospray ionization (ESI) in positive mode unless otherwise indicated. Calculated (calcd.) mass corresponds to the exact mass.

Nuclear magnetic resonance (NMR) spectra were obtained on Bruker model DRX spectrometers. The format of the ¹H NMR data below is: chemical shift in ppm downfield of the tetramethylsilane reference (multiplicity, coupling constant J in Hz, integration).

Chemical names were generated using ChemDraw Ultra 12.0 (CambridgeSoft Corp., Cambridge, Mass.) or ACD/Name Version 10.01 (Advanced Chemistry Development, Toronto, Ontario, Canada).

Where compounds were purified by “SFC Chromatography” the method employed was either:

On preparative APS 1010 system with autoprep otion from Berger instrument, consisted of two varian SD-1 pumps (walnut creek, CA, USA), one of which was extensively modified to pump CO₂, a special pump head heat exchanger, ajulabo FT 401 chiller (labortechnik GmbH, Sellback, Germany), a model SCM 2500 phase separator (berger instruments) with selection valve and set of collection vessels in a Bodan robot. A model Knauer 2500 UV detector with high pressure flow cell (berlin, germany). Sample were applied using a six-port injection valve (Valco, Houston, Tex., USA)) with a 5 ml sample loop and a model YP-300 syringue pump (cavro, san Jose, Calif.). or

On a SFC-PICLAB-PREP 200 (PIC SOLUTION, Avignon, France). Modifier was pump with a model K1800 Knauer (Berlin, germany), with 100 ml Pump Head. The CO₂ was pump with 2 lewa pumps (Leonberg Germany). Cooling of the pump head and the CO2 line was achieved by a coil alimented by a Huber chiller (Offenburg/Germany). Sample injections were made using 6 switching valves (Valco, Houston, Tex., USA) and a 5 ml sample loop. The system is managed by a PLC automation system.

Intermediates

Intermediate Name Structure Reference A-1 2-(2H-1,2,3-trizol- 2-yl)benzoic acid

Prepared according to WO 2011/050198 Intermediate 2. A-2 3-fluoro-2-(pyrimidin- 2-yl)benzoic acid

Prepared according to WO 2011/050198 Intermediate 50. A-3 6-methyl-2-(2H- 1,2,3-triazol-2- yl)nicotinic acid

Prepared according to WO 2011/050198 Intermediate70 A-4 6-methyl-2-(2H- 1,2,3-triazol-1- yl)nicotinic acid

Prepared according to WO 2011/050198 Intermediate 71 A-5 4-methoxy-2-(2H- 1,2,3-triazol-2- yl)benzoic acid

Prepared according to WO 2011/050198 Intermediate 54 A-6 2-fluoro-6- (pyrimidin-2- yl)benzoic acid

Prepared according to WO 2011/050198 Intermediate 14. A-7 5-fluoro-2- (pyrimidin-2- yl)benzoic acid.

Prepared according to WO 2011/050198 Intermediate 13. A-8 3-ethoxy-6- methylpicolinic acid

WO 2010/063663 Description 39 A-9 6-methyl-3- (pyrimidin-2- yl)picolinic acid

WO 2010/063663 Description 69 A-10 5-fluoro-2-(2H- 1,2,3-triazol-2- yl)benzoic acid

Prepared according to WO 2011/050198 Intermediate 1. A-11 2-fluoro-6-(2H- 1,2.3-triazol-2- yl)benzoic acid

Prepared according to WO 2011/050198 Intermediate 12. A-12 4-fluoro-2-(2H- 1,2,3-triazol-2- yl)benzoic acid

Prepared according to WO 2011/050198 Intermediate 4. A-13 2-methoxy-6-(2H- 1,2,3-triazol-2- yl)benzoic acid

Prepared analogous to Intermediate A-X using 2-bromo-6- (2H-1,2,3-triazol- 2-yl)benzoic acid A-14 2-methyl-6-(2H- 1,2,3-triazol-2- yl)benzoic acid

Prepared according to WO 2011/050198 Intermediate 82. A-15 4-methoxy-2- (pyrimidin-2- yl)benzoic acid

Prepared according to WO 2011/050198 Intermediate 88. A-16 3-fluoro-2-(2H- 1,2,3-triazol-2- yl)benzoic acid

Prepared according to WO 2011/050198 Intermediate 5. A-17 3-fluoro-2-(3- methyl-1,2,4- oxadiazol-5- yl)benzoic acid

Prepared according to WO 2011/050198 Intermediate 63. A-18 5-methoxy-2-(2H- 1,2,3-triazol-2- yl)benzoic acid

Prepared according to WO 2011/050198 Intermediate 10

Synthesis of 3-fluoro-2-(pyrimidin-2-yl)benzonitrile (Intermediate in the synthesis of intermediate A-2)

To a solution of 3-fluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile (4.98 g, 19.1 mmol) and 2-bromopyridine (3.85 g, 23 mmol) in THF (96 mL) was added Na₂CO₃ (6 g, 57.4 mmol) followed by water (43 mL). The reaction mixture was degassed with N₂ for 10 minutes. PdCl₂(dtbpf) (374 mg, 0.57 mmol) was added and the reaction mixture was stirred at 80° C. for 5 h. The solution was cooled to room temperature and a mixture of EtOAc and water was added. The aqueous was extracted twice with EtOAc and the combined organic layers were dried over MgSO4, filtered and evaporated. The title compound was precipitated by dissolving the residue in a minimum amount of EtOAc and then adding hexanes. The solid was filtered, washed with hexanes and dried to afford the title compound (2.46 g, 64%). MS (ESI) mass calcd. for C₁₁H₆FN₃, 199.1; m/z found 200.1 [M+H]⁺. ¹H NMR (400 MHz, Chloroform-d) δ 9.02-8.91 (m, 2H), 7.65 (dt, J=7.7, 1.0 Hz, 1H), 7.60-7.52 (m, 1H), 7.51-7.43 (m, 1H), 7.41 (t, J=4.9 Hz, 1H).

Intermediate A-19: 5-methyl-3-(2H-1,2,3-triazol-2-yl)picolinic acid

Step A: 5-methyl-3-(2H-1,2,3-triazol-2-yl)picolinonitrile. To 3-bromo-5-methylpicolinonitrile (1.5 g, 7.6 mmol) in DMF (19 mL) was added K₂CO₃ (1.2 g, 8.4 mmol) and 2H-1,2,3-triazole (440 μL, 7.6 mmol). The mixture was heated to 100° C. for 16 h, cooled to rt and extracted with EtOAc (2×). The combined organics were dried (Na₂SO₄) and concentrated. Purification via silica gel chromatography (5-60% EtOAc in hexanes) gave the title compound (490 mg, 35%) ¹H NMR (500 MHz, CDCl₃) 8.58-8.53 (m, 1H), 8.29-8.24 (m, 1H), 7.98 (s, 2H), 2.54 (s, 3H) and 5-methyl-3-(1H-1,2,3-triazol-1-yl)picolinonitrile (387 mg, 27%).

Step B: 5-methyl-3-(2H-1,2,3-triazol-2-yl)picolinate. To a solution of the title compound of Step A (489 mg, 2.6 mmol) in EtOH (7 mL) was added 4 N NaOH (660 μL, 2.6 mmol). The mixture was heated at 100° C. for 24 h. The reaction mixture was concentrated in vacuo to a white solid which was used without further purification in subsequent steps. MS (ESI) mass calcd. for C₉H₈N₄O₂, 204.1; m/z found 205.0 [M+H]⁺.

Intermediate A-20: 5-methyl-3-(1H-1,2,3-triazol-1-yl)picolinic acid

Step A: 5-methyl-3-(1H-1,2,3-triazol-1-yl)picolinonitrile. The title compound was prepared in Intermediate A-19 Step A. ¹H NMR (500 MHz, CDCl₃) 8.65 (dd, J=1.8, 0.9 Hz, 1H), 8.41 (d, J=1.2 Hz, 1H), 8.18-8.15 (m, 1H), 7.95 (d, J=1.2 Hz, 1H), 2.58 (s, 3H).

Step B: 5-methyl-3-(1H-1,2,3-triazol-1-yl)picolinic acid. Prepared analogous to Intermediate A-19 substituting 5-methyl-3-(2H-1,2,3-triazol-2-yl)picolinonitrile with the title compound of Step A. MS (ESI) mass calcd. for C₉H₈N₄O₂, 204.1; m/z found 205.0 [M+H]⁺.

Intermediate A-21: 6-methyl-3-(2H-1,2,3-triazol-2-yl)picolinic acid

Step A: 6-methyl-3-(2H-1,2,3-triazol-2-yl)picolinonitrile. To 3-bromo-5-methylpicolinonitrile (2.2 g, 11 mmol) in DMF (28 mL) was added K₂CO₃ (1.7 g, 12 mmol) and 2H-1,2,3-triazole (650 μL, 11 mmol). The mixture was heated to 100° C. for 36 h, cooled to rt and extracted with EtOAc. The combined organics were dried (Na₂SO₄) and concentrated. Purification via silica gel chromatography (10-100% EtOAc in hexanes) gave the title compound (1 g, 48%).

Step B: 6-methyl-3-(2H-1,2,3-triazol-2-yl)picolinic acid. To a solution of the title compound of Step A (730 mg, 4 mmol) in EtOH (10 mL) was added 4 N NaOH (1 mL, 4 mmol). The mixture was heated at 100° C. for 24 h. The reaction mixture was concentrated in vacuo to a white solid which was used without further purification in subsequent steps.

Intermediate A-22: 3-ethoxyisoquinoline-4-carboxylic acid

Step A: ethyl 3-hydroxyisoquinoline-4-carboxylate. To a suspension of ethyl 3-aminoisoquinoline-4-carboxylate (583 mg, 2.70 mmol) in 6.8 mL of H₂SO₄ 5N cooled to 0° C. was added sodium nitrite (223 mg, 3.24 mmol, dissolved in 1 mL of water). The reaction mixture was stirred at 0° C. for 2.5 h and then NaOH_((aq)) 1N was added until pH=7. The aqueous phase was extracted twice with DCM and the combined organic phases were dried over MgSO₄, filtered and evaporated to give the title compound of Step A which was used without further purification in the next step (583 mg, 99%). MS (ESI) mass calcd. for C₁₂H₁₁NO₃, 217.1; m/z found 218.1 [M+H]⁺.

Step B: ethyl 3-ethoxyisoquinoline-4-carboxylate. To the title compound of Step A (583 mg, 2.68 mmol) in THF (13 mL) was added triphenylphosphine (1.06 g, 4.03 mmol), ethanol (0.24 mL, 4.03 mmol) and DIAD (0.79 mL, 4.03 mmol). The reaction mixture was stirred at room temperature for 16 h and then the solvent was evaporated. The crude was purified via silica gel chromatography (0-30% EtOAc in hexanes) to afford the title compound of Step B (498 mg, 76%). MS (ESI) mass calcd. for C₁₄H₁₅NO₃, 245.1; m/z found 246.1 [M+H]⁺. ¹H NMR (500 MHz, Chloroform-d) δ 8.97 (s, 1H), 7.91-7.82 (m, 2H), 7.65-7.60 (m, 1H), 7.42-7.36 (m, 1H), 4.59-4.48 (m, 4H), 1.48-1.39 (m, 6H).

Step C: 3-ethoxyisoquinoline-4-carboxylic acid. The title compound of Step B (492 mg, 2 mmol) dissolved in MeOH (15 mL) was added NaOH_((aq)) 2M (2.5 mL). The reaction mixture was stirred at 60° C. for 16 h and then NaOH_((aq)) 4M (2 mL) was added and the mixture was stirred at 70° C. for 4 h. MeOH was evaporated and the aqueous phase was cooled to 0° C. and acidified with the addition of HCl_((aq)) 6N. The solid was filtered, washed with cold water and dried to afford the title compound (285 mg, 65%). MS (ESI) mass calcd. for C₁₂H₁₁NO₃, 217.1; m/z found 218.1 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d6) δ 13.36 (s, 1H), 9.15 (s, 1H), 8.13-8.06 (m, 1H), 7.82-7.70 (m, 2H), 7.54-7.47 (m, 1H), 4.50 (q, J=7.0 Hz, 2H), 1.35 (t, J=7.0 Hz, 3H).

Intermediate A-23: 4-(difluoromethoxy)-2-(2H-1,2,3-triazol-2-yl)benzoic acid

Prepared analogous to Intermediate A-19 substituting 2-bromo-6-methyl-3-(2H-1,2,3-triazol-2-yl)pyridine with 4-(difluoromethoxy)-2-fluorobenzonitrile.

Intermediate Name Structure Reference A-24 3-methyl-2-(2H-1,2,3- triazol-2-yl)benzoic acid

Prepared according to WO 2011/050198 Intermediate 82 A-25 4-fluoro-2-(pyrimidin-2- yl)benzoic acid

Prepared according to WO 2011/050198 Intermediate 87

Intermediate A-26: 3-methyl-2-(pyrimidin-2-yl)benzoic acid

Step A: methyl 3-methyl-2-(pyrimidin-2-yl)benzoate. In a microwave vial was dissolved methyl 3-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (619 mg, 2.24 mmol) and 2-chloropyrimidine (314 mg, 2.69 mmol) in 2-MeTHF (10 mL). Na₂CO₃ (713 mg, 6.73 mmol) was then added followed by water (3.4 mL) and the reaction mixture was degassed with N₂ for 45 minutes. Pd(dppf)Cl₂ (66 mg, 0.09 mmol) and the reaction mixture was heated at 75° C. for 28 h. More Pd(dppf)Cl₂ (33 mg, 0.045 mmol) was added and the reaction mixture was heated at 150° C. for 3.5 h. The mixture was filtered through a pad of celite and rinsed with EtOAc and water. The layers were separated and the aqueous was extracted once with EtOAc. The combined organic layers were dried over MgSO₄, filtered and evaporated. The crude was purified via silica gel chromatography (0-50% EtOAc in hexanes) to afford the title compound (116 mg, 23%). MS (ESI) mass calcd. for C₁₃H₁₂N₂O₂, 228.1; m/z found 229.1 [M+H]⁺. ¹H NMR (500 MHz, CDCl3) 8.95-8.76 (m, 2H), 7.99-7.75 (m, 1H), 7.50-7.44 (m, 1H), 7.43-7.37 (m, 1H), 7.32-7.24 (m, 1H), 3.64 (s, 3H), 2.15 (s, 3H).

Step B: 3-methyl-2-(pyrimidin-2-yl)benzoic acid. Prepared analogous to intermediate A-31 step B to give title compound. MS (ESI) mass calcd. for C₁₂H₁₀N₂O₂, 214.1; m/z found 215.1 [M+H]⁺.

Intermediate Name Structure Reference A-27 3-(2H-1,2,3- triazol-2- yl)picolinic acid

Prepared according to WO 2011/050198 Intermediate 72

Intermediate A-28: 2-methoxy-6-(pyrimidin-2-yl)benzoic acid

Step A: Methyl 2-methoxy-6-(pyrimidin-2-yl)benzoate. In a microwave vial was dissolved methyl 2-methoxy-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (500 mg, 1.71 mmol), commercially available from Combi-Blocks (CAS #1146214-77-8), and 2-bromopyrimidine (344 mg, 2.05 mmol) in THF (8.5 mL). Na₂CO₃ (544 mg, 5.14 mmol) was then added followed by water (4 mL) and the reaction mixture was degassed with N₂ for 10 minutes. PdCl₂(dtbpf) (45 mg, 0.069 mmol) was then added and the reaction mixture was heated at 80° C. for 4 h. The mixture was cooled to room temperature and water and EtOAc added. The reaction mixture was extracted with EtOAc (3×). The combined organic layers were dried over Na₂SO₄, filtered, and concentrated. The crude was purified via silica gel chromatography (0-70% EtOAc in hexanes) to afford the title compound (265 mg, 63%). MS (ESI) mass calcd. for C₁₃H₁₂N₂O₃, 244.1; m/z found 245.1 [M+H]⁺. ¹H NMR (400 MHz, Chloroform-d) 8.78 (d, J=4.9 Hz, 2H), 7.99 (dd, J=7.9, 0.9 Hz, 1H), 7.49 (t, J=8.1 Hz, 1H), 7.19 (t, J=4.8 Hz, 1H), 7.09 (dd, J=8.3, 0.9 Hz, 1H), 3.90 (s, 3H), 3.89 (s, 3H).

Step B: 2-methoxy-6-(pyrimidin-2-yl)benzoic acid. To a solution of the title compound of Step A (265 mg, 1.09 mmol) in THF (4 mL) was added 2 N NaOH (2 mL). The mixture was heated at 50° C. for 72 h. The reaction mixture was concentrated in vacuo to a white solid which was used without further purification in subsequent steps. MS (ESI) mass calcd. for C₁₂H₁₀N₂O₃, 230.1; m/z found 231.1 [M+H]⁺. ¹H NMR (500 MHz, DMSO-d₆) 12.63 (s, 1H), 8.86 (d, J=4.9 Hz, 2H), 7.77 (dd, J=7.9, 1.0 Hz, 1H), 7.51 (t, J=8.1 Hz, 1H), 7.45 (t, J=4.9 Hz, 1H), 7.25 (dd, J=8.4, 1.0 Hz, 1H), 3.83 (s, 3H).

Intermediate A-29: 7-ethoxyquinoline-8-carboxylic acid

Step A: 7-methoxyquinoline-8-carboxylic acid. In 1 g separate batches a mixture of 2-amino-6methoxybenzoic acid (11 g, 66 mmol) and acrolein (4.8 mL, 72 mmol) in 1,4-dioxane (66 mL) was heated in a microwave reactor for 20 min at 200° C. After combining the reactions, the mixture was concentrated and purified via silica gel chromatography (0-10% MeOH in DCM) to give the title compound (2.8 g, 20%). MS (ESI) mass calcd. for C₁₁H₁₉NO₃, 203.1; m/z found 204.0 [M+H]⁺.

Step B: 7-hydroxyquinoline-8-carboxylic acid. The title compound of Step A (2.9 g, 14.1 mmol) in HBr (14 mL) was heated at 90° C. for 1 h. The mixture was then concentrated washed with PhCH3 and used without further purification in subsequent steps.

Step C: ethyl 7-ethoxyquinoline-8-carboxylate. To the title compound of Step B (800 mg, 3.9 mmol) and K₂CO₃ (1.4 g, 10.4 mmol) in DMF (15 mL) was added iodoethane (560 μL, 6.9 mmol). After stirring overnight at rt, the reaction was concentrated and purified via silica gel chromatography (0-30% EtOAc in hexanes) to give the title compound. MS (ESI) mass calcd. for C₁₄H₁₅NO₃, 245.1; m/z found 246.0 [M+H]⁺.

Step D: 7-ethoxyquinoline-8-carboxylic acid. To the title compound of Step C (1.3 g, 5.4 mmol) in THF (22 mL) and H₂O (11 mL) was added LiOH hydrate (675 mg, 16.5 mmol) and MeOH. The mixture was heated at 67° C. for 12 h. Additional LiOH hydrate (675 mg, 16.5 mmol) was added and the heating was continued at 70° C. for 1 days. Additional LiOH hydrate (1.4 g, 33 mmol) was added and the heating was continued at 75° C. for 1 day. The reaction was allowed to cool to rt, acidified to pH=3 with 1N HCl (aq) and concentrated. Purification via prep HPLC gave the title compound (1 g, 84%). MS (ESI) mass calcd. for C₁₂H₁₁NO₃, 217.1; m/z found 218.0 [M+H]⁺.

Intermediate A-30: 2-(1,4-dimethyl-1H-pyrazol-5-yl)-6-methoxybenzoic acid

Step A: Ethyl 2-(1,4-dimethyl-1H-pyrazol-5-yl)-6-methoxybenzoate. In a microwave vial was dissolved ethyl 2-bromo-6-methoxybenzoate (500 mg, 1.54 mmol) and 1,4-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (377 mg, 1.70 mmol) in DME (10 mL) and water (2 mL). Na₂CO₃ (259 mg, 3.09 mmol) was then added followed by Pd(PPh₃)₄ (89 mg, 0.077 mmol) and the reaction mixture was degassed with N₂ for 10 minutes. The reaction mixture was then heated at 100° C. for 1 h in the microwave. The mixture was cooled to room temperature, filtered through Celite and washed with EtOAc and DCM. The crude solution was concentrated in vacuo and directly purified via silica gel chromatography (10-80% EtOAc in hexanes) to afford the title compound (402 mg, 95%). MS (ESI) mass calcd. for C₁₅H₁₈N₂O₃, 274.1; m/z found 275.2 [M+H]⁺. 1H NMR (400 MHz, Chloroform-d) 7.45 (dd, J=8.4, 7.6 Hz, 1H), 7.29 (s, 1H), 7.04 (dd, J=8.5, 0.9 Hz, 1H), 6.84 (dd, J=7.6, 0.9 Hz, 1H), 4.07 (qd, J=7.2, 1.5 Hz, 2H), 3.90 (s, 3H), 3.61 (s, 3H), 1.86 (s, 3H), 1.01 (t, J=7.1 Hz, 3H).

Step B: 2-(1,4-dimethyl-1H-pyrazol-5-yl)-6-methoxybenzoic acid. Prepared analogous to intermediate A-28 step B to give title compound. MS (ESI) mass calcd. for C₁₃H₁₄N₂O₃, 246.1; m/z found 247.2 [M+H]⁺. ¹H NMR (500 MHz, DMSO-d₆) 7.50 (dd, J=8.5, 7.6 Hz, 1H), 7.25 (s, 1H), 7.21 (dd, J=8.5, 0.9 Hz, 1H), 6.85 (dd, J=7.6, 0.9 Hz, 1H), 3.84 (s, 3H), 3.49 (s, 3H), 1.79 (s, 3H).

Intermediate A-31: 3-methyl-2-(oxazol-2-yl)benzoic acid

Step A: ethyl 3-methyl-2-(oxazol-2-yl)benzoate. In a microwave vial was dissolved ethyl 2-iodo-3-methylbenzoate (627 mg, 2.16 mmol) and 2-(tributylstannyl)oxazole (0.54 mL, 0.07 mmol) in DME (2.59 mL). The solution was degassed with N₂ for 5 minutes then CuI (21 mg, 0.11 mmol) and Pd(PPh₃)₄ (125 mg, 0.11 mmol) were added. The reaction was purged with N₂ and heated at 150° C. for 1 h. The reaction was cooled to rt, filtered through a pad of celite and purified via silica gel chromatography (0-40% EtOAc in hexanes) to give the title compound of step A (333 mg, 67%). MS (ESI) mass calcd. for C₁₃H₁₃NO₃, 231.1; m/z found 232.1 [M+H]⁺. ¹H NMR (500 MHz, Chloroform-d) 7.89-7.82 (m, 1H), 7.79 (d, J=0.8 Hz, 1H), 7.48-7.43 (m, 2H), 7.30 (d, J=0.9 Hz, 1H), 4.17 (q, J=7.1 Hz, 2H), 2.27 (s, 3H), 1.18 (t, J=7.1 Hz, 3H).

Step B: 3-methyl-2-(oxazol-2-yl)benzoic acid. To the title compound of step A (166 mg, 0.72 mmol) was added MeOH (7.2 mL) and 1M NaOH_((aq)) (7.2 mL). MeOH was evaporated and then 1 M HCl_((aq)) was added. To the solution was added DCM and the aqueous was extracted with DCM (3×). The combined organic layers were dried over MgSO₄, filtered and evaporated to give the title compound (145 mg). MS (ESI) mass calcd. for C₁₁H₉NO₃, 203.1; m/z found 204.1 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.20 (s, 1H), 7.79-7.68 (m, 1H), 7.65-7.49 (m, 2H), 7.35 (s, 1H), 4.34 (s, 1H), 2.20 (s, 3H).

Intermediate A-32: 4-methyl-3-(2H-1,2,3-triazol-2-yl)picolinic acid

Step A: 4-methyl-3-(2H-1,2,3-triazol-2-yl)picolinonitrile. In a microwave vial was dissolved 2H-1,2,3-triazole (0.22 mL, 3.8 mmol) and CuI (26 mg) in DMF (4 mL). The reaction mixture was degassed with N₂ and 3-bromo-4-methylpicolonitrile (300 mg, 1.5 mmol) was added followed by trans-N,N′-dimethyl-1,2-cyclohexanediamine (41 μL, 0.3 mmol) and Cs₂CO₃ (844 mg, 2.6 mmol). The reaction mixture was heated at 120° C. for 1 h in a microwave reactor. Then H₂O was added and the mixture extracted with EtOAc. The combined organic layers were dried (MgSO₄). Purification via silica gel chromatography (0-50% EtOAc in heptane) gave the title compound (112 mg, 27%). MS (ESI) mass calcd. for C₉H₇N₅, 185.2; m/z found 186 [M+H]⁺.

Step B: 4-methyl-3-(2H-1,2,3-triazol-2-yl)picolinic acid. Prepared analogous to Intermediate A-19 substituting 5-methyl-3-(2H-1,2,3-triazol-2-yl)picolinonitrile with the title compound of Step A. The reaction mixture was acidified to pH=4 before concentrating. MS (ESI) mass calcd. for C₁₁H₉NO₃, 203.1; m/z found 204.1 [M+H]⁺.

Intermediate A-33: 3-(2H-1,2,3-triazol-2-yl)quinoline-2-carboxylic acid

Step A: ethyl 3-(2H-1,2,3-triazol-2-yl)quinoline-2-carboxylate. Prepared analogous to Intermediate A-40 Step A substituting 2-bromo-4-methylbenzoic acid with ethyl 3-iodoquinoline-2-carboxylate (WO 2011093365) in <10% yield. MS (ESI) mass calcd. for C₁₄H₁₂N₄O₂, 268.3; m/z found 269.0 [M+H]⁺.

Step B: 3-(2H-1,2,3-triazol-2-yl)quinoline-2-carboxylic acid. To the title compound of Step A (134 mg, 0.5 mmol) in MeOH (1 mL) was added aqueous 2M NaOH (1 mL). After 1 h at rt, the reaction was heated to 50° C. for 1 h, cooled to rt, acidified with 1N HCl, concentrated and used in subsequent steps without further purification. MS (ESI) mass calcd. for C₁₂H₈N₄O₂, 240.2; m/z found 241.0 [M+H]⁺.

Intermediate Name Structure Reference A-34 5-methyl-2- (pyrimidin-2- yl)benzoic acid

Prepared according to WO 2011/050198 Intermediate 50. A-35 2-methyl-6- (pyrimidin-2- yl)benzoic acid

Prepared according to intermediate A-34 or A-2 A-36 4-methyl-2- (pyrimidin-2- yl)benzoic acid

Prepared according to intermediate A-34 or A-2 A-37 5-methyl-2-(2H-1,2,3- triazol-2-yl)benzoic acid

Prepared according to WO 2011/050198 Intermediate 8. A-38 5-chloro-2-(2H-1,2,3- triazol-2-yl)benzoic acid

Prepared according to WO 2011/050198 Intermediate 9. A-39 5-fluoro-2-(1H- pyrazol-5-yl)benzoic acid

Prepared according to WO 2011/050198 Intermediate 51.

Intermediate A-40: 4-methyl-2-(2H-1,2,3-triazol-2-yl)benzoic acid

Step A: 4-methyl-2-(2H-1,2,3-triazol-2-yl)benzoic acid and 4-methyl-2-(1H-1,2,3-triazol-1-yl)benzoic acid. In a microwave vial was dissolved 2H-1,2,3-triazole (0.34 mL, 5.81 mmol) and CuI (40 mg, 0.21 mmol) in DMF (5 mL). The reaction mixture was degassed with N₂ for 10 minutes and 2-bromo-4-methylbenzoic acid (500 mg, 2.33 mmol) was added followed by trans-N,N′-dimethyl-1,2-cyclohexanediamine (62 μL, 0.40 mmol) and Cs₂CO₃ (1.29 g, 3.95 mmol). The reaction mixture was stirred at 100° C. for 20 minutes using a microwave oven before being partitioned between water, HCl_((aq)) (pH=3) and EtOAc. The organic layer was dried over MgSO₄, filtered and evaporated to give the crude product mixture which was used in the next step without any further purification.

Step B: methyl 4-methyl-2-(2H-1,2,3-triazol-2-yl)benzoate. To the title compound of step A (945 mg, 4.65 mmol) in DMF (28 mL) was added K2CO3 (1.3 g, 9.3 mmol) and iodomethane (0.3 mL, 4.7 mmol). The reaction mixture was stirred at room temperature for 16 h under N₂. The solvent was evaporated and the residue was dissolved with a saturated solution of NaHCO₃. The aqueous phase was extracted with DCM and the organic layer was dried over MgSO4, filtered and evaporated. The crude material was purified via silica gel chromatography (0% to 30% EtOAc/heptane) to afford the title compound (470 mg, 47%).

Step C: Prepared analogous to Intermediate A-31 step B substituting ethyl 3-methyl-2-(oxazol-2-yl)benzoate with the title compound of Step B and used without further purification in subsequent steps.

Intermediate Name Structure Reference A-41 2-(3-methyl-1,2,4- oxadiazol-5-yl)benzoic acid

Prepared analogous to intermediate A-17

Intermediate A-42: 3,6′-dimethyl-[2,3′-bipyridine]-2′-carboxylic acid

Step A: 3-bromo-6-methylpicolinic acid. To 3-bromo-6-methylpicolinonitrile (4 g, 20.3 mmol) in EtOH (40 mL) in a sealed tube was added aqueous 4M NaOH (15 mL). The reaction was heated at 90° C. for 24 h. Additional aqueous 4M NaOH was added and heating continued at 90° C. for 24 h. The reaction was cooled to rt, acidified to pH=3 with 1N HCl (aq), concentrated and used without further purification in subsequent steps. MS (ESI) mass calcd. for C₇H₆BrNO₂, 216.0; m/z found 218 [M+H]⁺.

Step B: Methyl 3-bromo-6-methylpicolinate. To the title compound of step A (10.3 g, 20 mmol) in MeOH (50 mL) was added thionyl chloride (4.4 mL, 60 mmol). The reaction was heated at reflux overnight, cooled to rt and concentrated. Purification via silica gel chromatography (0-15% EtOAc in heptane) gave the title compound (1.9 g, 40%). MS (ESI) mass calcd. for C₈H₈BrNO₂, 230.1; m/z found 232 [M+H]⁺.

Step C: 3-methyl-2-(tributylstannyl)pyridine. To 2-bromo-3-methylpyridine (1.3 mL, 11.7 mmol) in THF (35 mL) at −78° C. was added n-BuLi (2.5 M in hexanes, 5.6 mL, 14 mmol). After 30 min, tri-n-butyltin chloride (3.8 mL, 14 mmol) was added. After 1 h at −78° C., the reaction was allowed to warm to rt. EtOAc was added and the reaction mixture was washed with 10% aq KF. The organic layer was dried (MgSO₄). Purification via silica gel chromatography (0-15% EtOAc in heptane) gave the title compound (1.2 g, 27%). MS (ESI) mass calcd. for C₁₈H₃₃NSn, 382.2; m/z found 384.0 [M+H]⁺.

Step D: methyl 3,6′-dimethyl-[2,3′-bipyridine]-2′-carboxylate. To the title compound of step B (509 mg, 2.2 mmol) and the title compound of step C (1.1 g, 2.9 mmol) in PhCH3 (6.6 mL) was added Pd(PPh₃)₄ (225 mg, 0.2 mmol). The reaction was degassed with N₂ and heated at 150° C. for 1.5 h using microwave reactor. The reaction was cooled to rt, diluted with H2O and extracted with EtOAc. The organic layer was dried (MgSO₄). Purification via silica gel chromatography (0-100% EtOAc in heptane) gave the title compound (101 mg, 18%). MS (ESI) mass calcd. for C₁₄H₁₄N₂O₂, 242.3; m/z found 243 [M+H]⁺.

Step E: 3,6′-dimethyl-[2,3′-bipyridine]-2′-carboxylic acid. Prepared analogous to intermediate A-33 step B substituting ethyl 3-(2H-1,2,3-triazol-2-yl)quinoline-2-carboxylate with the title compound of step D. MS (ESI) mass calcd. for C₁₃H₁₂N₂O₂, 228.2; m/z found 229 [M+H]⁺.

Intermediate A-43: 6-methyl-3-(oxazol-2-yl)picolinic acid

Prepared analogous to Intermediate A-31 substituting ethyl 2-iodo-3-methylbenzoate with methyl 3-iodo-6-methylpicolinate. MS (ESI) mass calcd. for C₁₀H₈N₂O₃, 204.2; m/z found 161 [M-CO2]⁺.

Intermediate Name Structure Reference A-44 6-methyl-3-(3- methyl-1,2,4- oxadiazol-5- yl)picolinic acid

WO 2010/063663 Description 64 A-45 6-methyl-3-(3- methyl-1H-pyrazol- 1-yl)picolinic acid

WO 2010/063663 Description 71 A-46 6-methyl-3-(4- methyl-1H-pyrazol- 1-yl)picolinic acid

WO 2010/063663 A-47 6-methyl-3-(1H- pyrazol-1- yl)picolinic acid

WO 2010/063663 Description 73 A-48 6-methyl-3-(3- methylisoxazol-5- yl)picolinic acid

WO 2010/063663 Description 117 A-49 1-methyl-3-phenyl- 1H-pyrazole-4- carboxylic acid

Purchased A-50 1-methyl-4-phenyl- 1H-pyrazole-5- carboxylic acid

Purchased A-51 1-methyl-5-phenyl- 1H-pyrazole-5- carboxylic acid

Purchased A-52 5-chloro-3-(2H- 1,2,3-triazol-2- yl)picolinic acid

WO 2012/145581 Intermediate 105 A-53 5-methoxy-3-(2H- 1,2,3-triazol-2- yl)picolinic acid

WO 2012/145581 Intermediate 105 A-54 6-methyl-3-(4- methyloxazol-2- yl)picolinic acid

Intermediate B-1: (±)-7-(tert-butoxycarbonyl)-7-azabicyclo[2.2.1]heptane-2-carboxylic acid

Prepared as described in as in WO 2004/074 292 A1. ¹H NMR (CDCl3): 4.54 (d, J=4.6 Hz, 1H), 4.33-4.24 (m, 1H), 2.61-2.18 (m, 4H), 1.90-1.71 (m, 2H), 1.68-1.57 (m, 1H), 1.56-1.35 (m, 10H).

Intermediates (+)-B-2 and (−)-B-2: (1S,2R,4R)-2-benzyl 7-tert-butyl 7-azabicyclo[2.2.1]heptane-2,7-dicarboxylate

And (1R,2S,4S)-2-benzyl 7-tert-butyl-7-azabicyclo[2.2.1]heptane-2,7-dicarboxylate

The title compounds were obtained by chiral SFC (CHIRALPAK IC 5 μM 250×20 mm) resolution of Intermediate B-3 (17 g) using 80% CO₂/20% iPrOH as the mobile phase to give (−)-B-3 enantiomer A (7.5 g, 1st eluting enantiomer) and enantiomer (+)-B3 (7.3 g, 2^(nd) eluting enantiomer).

Intermediate (−)-B-2: (−)-2-benzyl 7-tert-butyl-7-azabicyclo[2.2.1]heptane-2,7-dicarboxylate. Enantiomer A, [α]^(D) ₂₅−25.2 (c 2.8, CHCl₃).

Intermediate (+)-B-2: (+)-2-benzyl 7-tert-butyl-7-azabicyclo[2.2.1]heptane-2,7-dicarboxylate. Enantiomer B, [α]^(D) ₂₅+25.0 (c 2.8, CHCl₃). ¹H NMR (CDCl₃): 7.39-7.30 (m, 5H), 5.19-5.08 (m, 2H), 4.55 (s, 1H), 4.30 (s, 1H), 2.59 (dd, J=8.9, 5.0 Hz, 1H), 2.36-2.24 (m, 1H), 1.90-1.70 (m, 2H), 1.68-1.57 (m, 1H), 1.52-1.34 (m, 11H).

Intermediate B-3: (1S,2R,4R)-7-(tert-butoxycarbonyl)-7-azabicyclo[2.2.1]heptane-2-carboxylic acid

To intermediate (+)-B-2 (3.5 g, 10.6 mmol) in EtOH (100 mL) was added 10 wt % Pd/C wet Degussa (750 mg). The reaction was purged with N₂ followed by H₂, then allowed to proceed under an atmosphere of H₂ (balloon). Upon completion, the reaction was filtered and concentrated to give the title compound (2.4 g, 94%) that was used without further purification. ¹H NMR (CDCl₃): 4.62-4.52 (m, 1H), 4.35-4.26 (m, 1H), 2.59 (ddd, J=8.9, 5.0, 1.5 Hz, 1H), 2.29-2.19 (m, 1H), 1.91-1.71 (m, 2H), 1.68-1.58 (m, 1H), 1.54-1.35 (m, 11H).

Intermediate B-4: (1S,2R,4R)-tert-butyl 2-(((benzyloxy)carbonyl)amino)-7-azabicyclo[2.2.1]heptane-7-carboxylate

To intermediate B-3 (2.4 g, 9.9 mmol) in PhCH₃ (32 mL) was added TEA (1.5 mL, 10.9 mmol). After heating in an oil bath to 70° C., DPPA (2.4 mL, 10.9 mmol) in PhCH₃ (3 mL) was added. After 1 h, BnOH (1.0 g, 9.5 mmol) was added and the oil bath temperature increased to 90° C. After an additional 18 h, the reaction was cooled to rt, diluted with EtOAc and washed with saturated NaHCO₃ (aq). The aqueous layer was extracted with EtOAc (1×). The combined organics were washed with brine and dried (Na₂SO₄). Purification via silica gel chromatography (10-50% EtOAc in hexanes) gave the title compound (2.8 g, 78%). ¹H NMR (CDCl₃): 7.39-7.28 (m, 5H), 5.20-4.84 (m, 3H), 4.30-4.06 (m, 3H), 3.86-3.68 (m, 1H), 1.93 (dd, J=13.4, 8.1 Hz, 1H), 1.85-1.63 (m, 2H), 1.54-1.29 (m, 11H).

Intermediate B-5: (+)-(1S,2R,4R)-tert-butyl 2-amino-7-azabicyclo[2.2.1]heptane-7-carboxylate

To intermediate B-4 (400 mg, 1.2 mmol) in EtOH (5 mL) was added 10 wt % Pd/C wet Degussa (85 mg). The reaction was purged with N₂ followed by H₂, then allowed to proceed under an atmosphere of H₂ (balloon). Upon completion, the reaction was filtered and concentrated to give the title compound (244 mg, 99%) that was used without further purification. MS (ESI) mass calcd. for C₁₁H₂₀N₂O₂, 212.1; m/z found 213.1 [M+H]⁺. [α]^(D) ₂₅+9.8 (c 4.9, CHCl₃) ¹H NMR (CDCl3): 4.25-4.13 (m, 1H), 3.94-3.82 (m, 1H), 2.96 (dd, J=7.8, 3.0 Hz. 1H), 1.85-1.25 (m, 15H).

Intermediate B-6: (±)-tert-butyl 2-amino-7-azabicyclo[2.2.1]heptane-7-carboxylate

Prepared analogous to intermediate B-5 substituting intermediate B-4 with (±)-7-(tert-butoxycarbonyl)-7-azabicyclo[2.2.1]heptane-2-carboxylic acid (intermediate B-1).

Intermediate B-7: (±)-tert-butyl 2-amino-7-azabicyclo[2.2.1]heptane-7-carboxylate

Intermediate B-8: (−)-(1R,2S,4S)-tert-butyl 2-amino-7-azabicyclo[2.2.1]heptane-7-carboxylate

Prepared analogous to intermediate B-5 substituting enantiomer (1S,2R,4R)-2-benzyl 7-tert-butyl 7-azabicyclo[2.2.1]heptane-2,7-dicarboxylate (intermediate (+)-B-2) with enantiomer (1R,2S,4S)-2-benzyl 7-tert-butyl-7-azabicyclo[2.2.1]heptane-2,7-dicarboxylate (intermediate (−)-B-2).

Intermediate B-9: (1S,2R,4R)-tert-butyl 2-(hydroxymethyl)-7-azabicyclo[2.2.1]heptane-7-carboxylate

To intermediate (+)-B-2 (504 mg, 1.5 mmol) in THF (12 mL) at 0° C. was added Dibal-H (1M in THF, 4.6 mL). After 1 h, additional Dibal-H was added. The reaction allowed to warm to rt and quenched with Rochelle's Salt (20 wt %). EtOAc was added and the mixture allowed to stir until 2 clear layers had formed. The aqueous layer was extracted with EtOAc (2×). The combined organics were washed with brine and dried (Na₂SO₄). Purification via silica gel chromatography (10-50% EtOAc in hexanes) gave the title compound (171 mg, 49%). MS (ESI) mass calcd. for C₁₂H₂₁NO₃, 227.2; m/z found 228.2 [M+H]⁺, 172.2 [M−55]⁺. ¹H NMR (CDCl3): 4.26-4.12 (m, 2H), 3.45-3.32 (m, 2H), 3.00-2.04 (m, 1H). 1.95-1.90 (m, 1H), 1.83-1.73 (m, 2H), 1.53-1.37 (m, 12H), 1.32-1.28 (m, 1H).

Intermediate B-10: (±)-tert-butyl 2-(hydroxymethyl)-7-azabicyclo[2.2.1]heptane-7-carboxylate

As in Org. Syn., 1997, 74, 212, Tet. Lett. 1997, 38, 6829 and Biorg. Med. Chem. Lett. 2006, 14, 8219 ¹H NMR (CDCl₃): 4.25-4.13 (m, 2H), 3.47-3.32 (m, 2H), 1.98-1.68 (m, 4H), 1.56-1.26 (m, 13H).

Example 1: (5-fluoro-2-(pyrimidin-2-yl)phenyl)((1S,2R,4R)-2-((pyridin-2-yloxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Step A: (1S,2R,4R)-tert-butyl 2-((pyridin-2-yloxy)methyl)-7-azabicyclo[2.2.1]heptane-7-carboxylate. To intermediate B-9 (170 mg, 0.75 mmol) in DMF (3 mL) at 0° C. was added NaH (36 mg, 60 wt % in mineral oil, 0.9 mmol). After 30 min, 2-fluoropyridine (102 mg, 1.0 mmol) in DMF (0.5 mL) was added dropwise and the 0° C. ice bath was removed. The flask was then heated to 90° C. in an oil bath. After 2 h, ½ saturated NH₄Cl was added and the reaction extracted with EtOAc (2×). The combined organics were washed with brine and dried (Na₂SO₄). Purification via silica gel chromatography (5-30% EtOAc in hexanes) gave the title compound (172 mg, 76%) as a white solid. MS (ESI) mass calcd. for C₁₇H₂₄N₂O₃, 304.2; m/z found 305.1 [M+H]⁺. ¹H NMR (CDCl₃): 8.13 (dd, J=5.1, 2.0 Hz, 1H), 7.55 (ddd, J=8.7, 7.1, 2.0 Hz, 1H), 6.84 (dd, J=7.0, 5.0 Hz, 1H), 6.73 (d, J=8.3 Hz, 1H), 4.35-4.15 (m, 2H), 4.15-3.99 (m, 2H), 2.26-2.14 (m, 1H), 1.90-1.68 (m, 2H), 1.64-1.55 (m, 1H), 1.54-1.31 (m, 12H).

Step B: (1S,2R,4R)-tert-butyl-2-((pyridin-2-yloxy)methyl)-7-azabicyclo[2.2.1]heptane-7-carboxylate. To the title compound from Step A (130 mg, 0.4 mmol) in EtOAc was added 4M HCl in dioxane. After 3 h, the reaction was concentrated, neutralized with 5% Na₂CO₃ and extracted with DCM. The combined organics were dried (Na₂SO₄) to give the title compound from step B as a white solid that was used without further purification. MS (ESI) mass calcd. for C₁₂H₁₆N₂O, 204.1; m/z found 205.1 [M+H]⁺.

Step C: (5-fluoro-2-(pyrimidin-2-yl)phenyl)((1S,2R,4R)-2-((pyridin-2-yloxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)methanone. To the title compound of Step B (50 mg, 0.18 mmol) in DMF (1.4 mL) was added DIPEA (0.078 mL, 0.45 mmol), intermediate A-7 (43 mg, 0.2 mmol) and HATU (75 mg, 0.2 mmol). Upon completion of the reaction, purification was performed using Agilent prep method A to give the title compound. MS (ESI) mass calcd. for C₂₃H₂₁FN₄O₂, 404.2; m/z found 405.2 [M+H]⁺. ¹H NMR (CDCl₃): 8.78 (d, J=4.9 Hz, 1H), 8.71 (d, J=4.8 Hz, 1H), 8.26-8.21 (m, 2H), 7.60-7.50 (m, 1H), 7.23-7.00 (m, 3H), 6.90-6.82 (m, 1H), 6.78-6.71 (m, 0.5H), 6.59-6.51 (m, 0.5H), 4.88-4.78 (m, 1H), 4.26-4.09 (m, 1H), 4.09-3.95 (m, 1H), 3.92-3.79 (m, 1H), 2.39-2.18 (m, 1H), 2.04-1.86 (m, 1H), 1.81-1.31 (m, 5H).

Example 2: (±)-(6-methyl-3-(pyrimidin-2-yl)pyridin-2-yl)(2-((pyridin-2-yloxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 1 substituting intermediate B-9 with intermediate B-10, 5-fluoro-2-(pyrimidin-2-yl)benzoic acid with intermediate A-9 and HATU with HBTU to give the title compound. MS (ESI) mass calcd. for C₂₃H₂₃N₅O₂, 401.2; m/z found 402.2 [M+H]⁺. ¹H NMR (DMSO-D₆): 8.92 (d, J=4.9 Hz, 1H), 8.84 (d, J=4.9 Hz, 1H), 8.32 (t, J=8.3 Hz, 1H), 8.24 (dd, J=5.0, 1.4 Hz, 0.5H), 8.15 (dd, J=5.0, 1.5 Hz, 0.5H), 7.76-7.69 (m, 0.5H), 7.69-7.62 (m, 0.5H), 7.52-7.42 (m, 1.5H), 7.34 (d, J=8.1 Hz, 0.5H), 7.05-6.92 (m, 1H), 6.87 (d, J=8.3 Hz, 0.5H), 6.68 (d, J=8.3 Hz, 0.5H), 4.60-4.56 (m, 1H), 4.19 (td, J=10.3, 3.7 Hz, 1H), 4.06 (dt, J=10.4, 5.3 Hz, 1H), 3.86 (t, J=4.0 Hz, 0.5H), 3.77 (d, J=4.1 Hz, 0.5H), 2.56 (s, 1.5H), 2.39-2.15 (m, 1H), 2.06 (s, 1.5H), 1.88-1.33 (m, 6H).

Example 3A: (6-methyl-3-(pyrimidin-2-yl)pyridin-2-yl)((1S*,2R*,4R*)-2-((pyridin-2-yloxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

And Example 3B: (6-methyl-3-(pyrimidin-2-yl)pyridin-2-yl)((1R*,2S*,4S*)-2-((pyridin-2-yloxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

The title compounds were obtained by chiral SFC (CHIRALPAK AD-H 5 μM 250×20 mm) resolution of Example 2 (538 mg) using 70% CO₂/30% EtOH as the mobile phase to give enantiomer A (230 mg, 1st eluting enantiomer) and enantiomer B (226 mg, 2^(nd) eluting enantiomer). The enantiomeric purity was confirmed by analytical SFC using a CHIRALPAK AD (250×4.6 mm) and a mobile phase of 70% CO₂, 30% EtOH containing 0.3% iPrNH₂ over 7 minutes. (Example 3A: >98% single enantiomer, 4.00 min retention time; Example 3B>98% single enantiomer, 5.12 min retention time). Example 3A: MS (ESI) mass calcd. for C₂₃H₂₃N₅O₂, 401.2; m/z found 402.1 [M+H]⁺. ¹H NMR (CDCl₃): 8.83 (d, J=4.8 Hz, 0.8H), 8.72 (d, J=4.8 Hz, 1.2H), 8.43-8.37 (m, 1H), 8.19-8.09 (m, 1H), 7.59-7.48 (m, 1H), 7.28 (d, J=8.0 Hz, 0.4H), 7.19-7.16 (m, 1.6H), 6.88-6.81 (m, 1H), 6.76 (dt, J=8.4, 1.0 Hz, 0.4H), 6.57 (dt, J=8.3, 0.9 Hz, 0.6H), 4.92-4.84 (m, 1H), 4.38-4.23 (m, 1H), 4.17 (ddd, J=15.4, 10.3, 5.7 Hz, 1H), 3.97-3.87 (m, 1H), 2.62 (s, 1H), 2.39-2.18 (m, 2.5H), 2.11-1.81 (m, 2H), 1.74 (dd, J=12.3, 8.6 Hz, 0.5H), 1.68-1.36 (m, 4H).

Example 3B: MS (ESI) mass calcd. for C₂₃H₂₃N₅O₂, 401.2; m/z found 402.1 [M+H]⁺.

Example 4: (±)-(6-methyl-3-(2H-1,2,3-triazol-2-yl)pyridin-2-yl)(2-((pyridin-2-yloxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 1 substituting intermediate B-9 with intermediate B-10, intermediate A-7 with intermediate A-21 and HATU with HBTU to give the title compound. MS (ESI) mass calcd. for C₂₁H₂₂N₆O₂, 390.2; m/z found 391.2 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃): 8.20-8.07 (m, 2H), 7.84-7.75 (m, 2H), 7.61-7.49 (m, 1H), 7.31 (d, J=8.4 Hz, 0.4H), 7.19 (d, J=8.4 Hz, 0.6H), 6.87-6.83 (m, 1H), 6.76 (dt, J=8.4, 0.9 Hz, 0.4H), 6.57 (dt, J=8.3, 0.9 Hz, 0.6H), 4.91-4.81 (m, 1H), 4.32-4.07 (m, 2H), 3.96-3.84 (m, 1H), 2.62 (s, 1.2H), 2.40-2.17 (m, 2.8H), 2.13-1.94 (m, 1H), 1.94-1.68 (m, 1.8H), 1.68-1.37 (m, 3.2H).

Example 5A: (6-methyl-3-(2H-1,2,3-triazol-2-yl)pyridin-2-yl)((1S,2R,4R)-2-((pyridin-2-yloxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

And Example 5B: (6-methyl-3-(2H-1,2,3-triazol-2-yl)pyridin-2-yl)((1R,2S,4S)-2-((pyridin-2-yloxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

The title compounds were obtained by chiral SFC (CHIRALPAK AD-H 5 μM 250×20 mm) resolution of Example 4 (555 mg) using 70% CO₂/30% EtOH as the mobile phase to give enantiomer A (264 mg, 1st eluting enantiomer) and enantiomer B (248 mg, 2^(nd) eluting enantiomer). The enantiomeric purity was confirmed by analytical SFC using a CHIRALPAK AD (250×4.6 mm) and a mobile phase of 70% CO₂, 30% EtOH containing 0.3% iPrNH₂ over 7 minutes. (Example 5A: >98% single enantiomer, 2.80 min retention time; Example 5B>98% single enantiomer, 3.90 min retention time). Example 5A: MS (ESI) mass calcd. for C₂₁H₂₂N₆O₂, 390.2; m/z found 391.2 [M+H]⁺. Example 5B: MS (ESI) mass calcd. for C₂₁H₂₂N₆O₂, 390.2; m/z found 391.2 [M+H]⁺.

Example 6: (6-methyl-3-(2H-1,2,3-triazol-2-yl)pyridin-2-yl)((1S,2R,4R)-2-((pyridin-2-yloxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 1 substituting intermediate A-7 with intermediate A-21. MS (ESI) mass calcd. for C₂₁H₂₂N₆O₂, 390.2; m/z found 391.2 [M+H]⁺. [α]_(D) ²⁰+11.4° (c 0.88, CHCl₃). ¹H NMR (CDCl₃): 8.19-8.06 (m, 2H), 7.83-7.73 (m, 2H), 7.61-7.48 (m, 1H), 7.30 (d, J=8.4 Hz, 0.4H), 7.19 (d, J=8.4 Hz, 0.6H), 6.89-6.81 (m, 1H), 6.78-6.73 (m, 0.4H), 6.61-6.52 (m, 0.6H), 4.91-4.81 (m, 1H), 4.32-4.08 (m, 2H), 3.96-3.84 (m, 1H), 2.62 (s, 1.2H), 2.39-2.18 (m, 2.8H), 2.11-1.94 (m, 1.5H), 1.94-1.37 (m, 4.5H).

Example 7: (±)-(2-(((5-fluoropyridin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)(6-methyl-3-(2H-1,2,3-triazol-2-yl)pyridin-2-yl)methanone

Step A Method A: (±)-tert-butyl 2-(((5-fluoropyridin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptane-7-carboxylate. Tri-n-butylphosphine (1.8 mL, 7.8 mmol) was added to intermediate B-10 (830 mg, 3.7 mmol) and 5-fluoropyridin-2(1H)-one (500 mg, 4.4 mmol) in THF (11 mL) under nitrogen bubbling at rt. After 5 min of stirring, DEAD (1.4 mL, 7.1 mmol) was added and the mixture was stirred at 50° C. for 18 hours. The mixture was concentrated and purified silica gel chromatography (0-15% EtOAc in Heptane) to give the title compound of step A (590 mg, 45%) as a white solid.

Step A Method B: (±)-tert-butyl 2-(((5-fluoropyridin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptane-7-carboxylate. Prepared analogous to intermediate B-6 substituting intermediate B-9 with (±)-B-9 and 2-fluropyridine with 2,5-difluoropyridine. MS (ESI) mass calcd. for C₁₇H₂₃FN₂O₃, 322.2; m/z found 323.0 [M+H]⁺. ¹H NMR (CDCl₃): 8.02-7.87 (m, 1H), 7.41-7.27 (m, 1H), 6.70 (dd, J=9.1, 3.6 Hz, 1H), 4.39-4.10 (m, 2H), 4.09-3.89 (m, 2H), 2.25-2.09 (m, 1H), 1.91-1.26 (m, 15H).

Step B: (±)-2-(((5-fluoropyridin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptane. Prepared analogous to Example 1 substituting (±)-tert-butyl-2-((pyridin-2-yloxy)methyl)-7-azabicyclo[2.2.1]heptane-7-carboxylate with the title compound from Step A. ¹H NMR (CDCl₃): 7.96 (d, J=3.1 Hz, 1H), 7.33 (ddd, J=9.0, 7.6, 3.1 Hz, 1H), 6.70 (dd, J=9.0, 3.6 Hz, 1H), 4.09-3.98 (m, 2H), 3.72-3.56 (m, 2H), 2.22-1.99 (m, 3H), 1.72-1.53 (m, 3H), 1.49-1.34 (m, 1H).

Step C: (±)-(2-(((5-fluoropyridin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)(6-methyl-3-(2H-1,2,3-triazol-2-yl)pyridin-2-yl)methanone. Prepared analogous to Example 1 substituting 5-fluoro-2-(pyrimidin-2-yl)benzoic acid with 6-methyl-3-(2H-1,2,3-triazol-2-yl)picolinic acid. MS (ESI) mass calcd. for C₂₁H₂₁FN₆O₂, 408.2; m/z found 409.2.

Example 8A: ((1S,2R,4R)-2-(((5-fluoropyridin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)(6-methyl-3-(2H-1,2,3-triazol-2-yl)pyridin-2-yl)methanone

And Example 8B: ((1R,2S,4S)-2-(((5-fluoropyridin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)(6-methyl-3-(2H-1,2,3-triazol-2-yl)pyridin-2-yl)methanone

The title compounds were obtained by chiral SFC (CHIRALPAK AD-H 5 μM 250×20 mm) resolution of Example 7 (259 mg) using 70% CO₂/30% mixture of EtOH/i-PrOH (50/50 v/v) as the mobile phase to give enantiomer A (72 mg, 1st eluting enantiomer) and enantiomer B (84 mg, 2^(nd) eluting enantiomer). The enantiomeric purity was confirmed by analytical SFC using a CHIRALPAK AD-H (250×4.6 mm) and a mobile phase of 70% CO₂, 15% EtOH, 15% iPrOH containing 0.3% iPrNH₂ over 7 minutes. (Example 8A: 100% single enantiomer, 3.10 min retention time; Example 8B 100% single enantiomer, 4.58 min retention time). Example 8A: MS (ESI) mass calcd. for C₂₁H₂₁FN₆O₂, 408.2; m/z found 409.2 [M+H]⁺. Example 8B: MS (ESI) mass calcd. for C₂₁H₂₁FN₆O₂, 408.2; m/z found 409.2 [M+H]⁺.

Example 9: (±)-(2-(((5-fluoropyridin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)(5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone

Prepared analogous to Example 7 substituting intermediate A-21 with intermediate A-37. MS (ESI) mass calcd. for C₂₂H₂₂FN₅O₂, 407.2; m/z found 408.3 [M+H]⁺. ¹H NMR (CDCl₃): 8.03-7.95 (m, 1H), 7.81-7.70 (m, 3H), 7.38-7.11 (m, 3H), 6.72 (dd, J=9.0, 3.6 Hz, 0.5H), 6.52 (dd, J=9.0, 3.5 Hz, 0.5H), 4.86-4.74 (m, 1H), 4.15-3.68 (m, 3H), 2.46-2.37 (s, 1.6H), 2.32-1.78 (m, 4.4H), 1.72-1.22 (m, 4H).

Example 10A: ((1S,2R,4R)-2-(((5-fluoropyridin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)(5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone

And Example 10B: ((1R,2S,4S)-2-(((5-fluoropyridin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)(5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone

The title compounds were obtained by chiral SFC (CHIRALPAK AD-H 5 μM 250×20 mm) resolution of Example 9 (290 mg) using 60% CO₂/40% i-PrOH as the mobile phase to give enantiomer A (140 mg, 1st eluting enantiomer) and enantiomer B (134 mg, 2^(nd) eluting enantiomer). The enantiomeric purity was confirmed by analytical SFC using a CHIRALPAK AD-H (250×4.6 mm) and a mobile phase of 60% CO₂, 40% iPrOH containing 0.3% iPrNH₂ over 7 minutes. (Example 10A: >98% single enantiomer, 2.42 min retention time; Example 10B>98% single enantiomer, 3.20 min retention time).

Example 11: (±)-(2-(((5-fluoropyridin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)(2-(thiophen-2-yl)phenyl)methanone

To (±)-2-(((5-fluoropyridin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptane (35 mg, 0.2 mmol) in DCM (2.5 mL) was added TEA (25 μL, 0.2 mmol)) followed by 2-(thiophen-2-yl)benzoyl chloride (40 mg, 0.2 mmol) in DCM (2.5 mL). After 18 h, the reaction was diluted with DCM and washed with H₂O. The aqueous layer was extracted DCM (1×). The combined organics were dried (Na₂SO₄). Purification via silica gel chromatography (50-100% EtOAc in hexanes) gave the title compound (37 mg, 57%). MS (ESI) mass calcd. for C₂₃H₂₁FN₂O₂S, 408.1; m/z found 409.1 [M+H]⁺.

Example 12A: ((1S*,2R*,4R*)-2-(((5-fluoropyridin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)(2-(thiophen-2-yl)phenyl)methanone

And Example 12B: ((1R*,2S*,4S*)-2-(((5-fluoropyridin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)(2-(thiophen-2-yl)phenyl)methanone

The title compounds were obtained by chiral SFC (CHIRALPAK AS-H 5 μM 250×20 mm at 40° C.) resolution of Example 11 using 4.2 mL/min MeOH with 0.2% TEA, 37 mL/min CO₂ as the mobile phase to give enantiomer A (1st eluting enantiomer) and enantiomer B (2^(nd) eluting enantiomer).

Example 12A: MS (ESI) mass calcd. for C₂₃H₂₁FN₂O₂S, 408.2; m/z found 409.2 [M+H]⁺. ¹H NMR (CDCl₃): 7.97 (dd, J=11.0, 3.0 Hz, 1H), 7.54-7.20 (m, 6.5H), 7.01 (dd, J=5.0, 3.7 Hz, 1.5H), 6.71 (dd, J=9.1, 3.5 Hz, 0.5H), 6.45 (dd, J=9.0, 3.6 Hz, 0.5H), 4.83-4.63 (m, 1H), 4.18-3.38 (m, 3H), 2.70-0.40 (m, 7H).

Example 12B: MS (ESI) mass calcd. for C₂₃H₂₁FN₂O₂S, 408.2; m/z found 409.2 [M+H]⁺. ¹H NMR (CDCl₃): 7.97 (dd, J=11.0, 3.0 Hz, 1H), 7.54-7.20 (m, 6.5H), 7.01 (dd, J=5.0, 3.7 Hz, 1.5H), 6.71 (dd, J=9.1, 3.5 Hz, 0.5H), 6.45 (dd, J=9.0, 3.6 Hz, 0.5H), 4.83-4.63 (m, 1H), 4.18-3.38 (m, 3H), 2.70-0.40 (m, 7H).

Example 13: (±)-(5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl)(2-(((4-(trifluoromethyl)pyrimidin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Step A: (±)-7-azabicyclo[2.2.1]heptan-2-ylmethanol hydrochloride. To intermediate B-10 (1.1 g, 4.9 mmol) in MeOH (1 mL) was added 4M HCl in dioxane (3 mL). After 6 h, the reaction was concentrated to give the title compound that was used without further purification.

Step B: ((±)-2-(hydroxymethyl)-7-azabicyclo[2.2.1]heptan-7-yl)(5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone. To the title compound of Step A in DMF was added TEA, 5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoic acid and HATU. After 18 h, H₂O was added and the mix extracted with EtOAc (2×). The combined organics were washed with brine and dried (Na₂SO₄). Silica gel chromatography (1-7% 2M NH₃/MeOH in DCM) gave the title compound (371 mg, 46%). MS (ESI) mass calcd. for C₁₇H₂₀N₄O₂, 312.2; m/z found 313.2 [M+H]⁺.

Step C: (±)-(5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl)(2-(((4-(trifluoromethyl)pyrimidin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)methanone. To the title compound of step B (33 mg, 0.1 mmol) in THF (2 mL) was added NaOtBu (16 mg, 0.16 mmol). The reaction was then heated at reflux for 15 min and 2-chloro-4-trifluromethylpyrimidine (19 mg, 0.16 mmol) was added. The reaction was heated at reflux temperature for 1 h, cooled to rt, diluted with H₂O and extracted with DCM (2×). The combined organics were dried (Na₂SO₄). Purification via silica gel chromatography (0.5-4% 2M NH₃/MeOH in DCM gave the title compound (28 mg, 57%). MS (ESI) mass calcd. for C₂₂H₂₁F₃N₆O₂, 457.2; m/z found 458.2 [M+H]⁺. ¹H NMR (CDCl₃): 8.82-8.72 (m, 1H), 7.86-7.69 (m, 3H), 7.36-7.10 (m, 3H), 4.85 (m, 1H), 4.47 (t, J=10.1 Hz, 0.5H), 4.20-3.98 (m, 1.5H), 3.90 (d, J=4.7 Hz, 0.5H), 3.78 (t, J=4.5 Hz, 0.5H), 2.51-2.20 (m, 3H), 2.14-1.82 (m, 2H), 1.78-1.17 (m, 5H).

Example 14: (±)-(5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl)(2-(((5-(trifluoromethyl)pyridin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 13 substituting 2-chloro-4-(trifluoromethyl)pyrimidine with 2-chloro-5-(trifluoromethyl)pyridine. MS (ESI) mass calcd. for C₂₃H₂₂F₃N₅O₂, 457.2; m/z found 458.2 [M+H]⁺.

Example 15: (±)-(5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl)(2-(((3-(trifluoromethyl)pyridin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 13 substituting 2-chloro-4-(trifluoromethyl)pyrimidine with 2-chloro-3-(trifluoromethyl)pyridine. MS (ESI) mass calcd. for C₂₃H₂₂F₃N₅O₂, 457.2; m/z found 458.2 [M+H]⁺. ¹H NMR (CDCl₃): 8.36-8.26 (m, 1H), 7.91-7.69 (m, 4H), 7.36-7.29 (m, 0.5H), 7.25-7.16 (m, 1H), 7.13-7.07 (m, 0.5H), 6.97 (dd, J=7.5, 5.1 Hz, 1H), 4.87-4.70 (m, 1H), 4.53-4.34 (m, 0.5H), 4.25-4.06 (m, 1H), 3.92 (t, J=10.9 Hz, 0.5H), 3.85-3.71 (m, 1H), 2.46-2.40 (m, 1.5H), 2.39-2.19 (m, 1.5H), 2.04-1.79 (m, 3H), 1.72-1.19 (m, 4H).

Example 16: (±)-(5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl)(2-(((6-(trifluoromethyl)pyridin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 13 substituting 2-chloro-4-(trifluoromethyl)pyrimidine with 2-chloro-6-(trifluoromethyl)pyridine. MS (ESI) mass calcd. for C₂₃H₂₂F₃N₅O₂, 457.2; m/z found 458.2 [M+H]⁺. ¹H NMR (CDCl₃): 7.87-7.63 (m, 4H), 7.37-7.11 (m, 3H), 6.92 (d, J=8.4 Hz, 0.5H), 6.73 (d, J=8.4 Hz, 0.5H), 4.88-4.75 (m, 1H), 4.20-3.84 (m, 2H), 3.81-3.67 (m, 1H), 2.49-2.36 (s, 2H), 2.34-2.13 (m, 1H), 2.08-1.77 (m, 3H), 1.76-1.10 (m, 4H).

Example 17: (±)-(5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl)(2-(((4-methylpyridin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 13 substituting 2-chloro-4-(trifluoromethyl)pyrimidine with 2-chloro-4-(methyl)pyridine. MS (ESI) mass calcd. for C₂₃H₂₅N₅O₂, 403.2; m/z found 404.2 [M+H]⁺. ¹H NMR (CDCl₃): 8.10-7.91 (m, 1H), 7.87 (d, J=3.7 Hz, 2H), 7.82-7.70 (m, 1H), 7.50-7.42 (m, 1H), 7.34-7.24 (m, 0.5H), 7.16-7.08 (m, 0.5H), 6.90-6.80 (m, 1H), 6.77-6.66 (m, 0.4H), 6.59-6.45 (m, 0.6H), 4.68 (q, J=4.0, 3.3 Hz, 1H), 4.16-3.71 (m, 3H), 2.49-2.18 (m, 5H), 1.94-1.17 (m, 8H).

Example 18: (±)-(5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl)(2-(((6-methylpyridin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 13 substituting 2-chloro-4-(trifluoromethyl)pyrimidine with 2-chloro-6-(methyl)pyridine. MS (ESI) mass calcd. for C₂₃H₂₅N₅O₂, 403.2; m/z found 404.2 [M+H]⁺. ¹H NMR (CDCl₃): 7.89 (d, J=1.3 Hz, 2H), 7.82-7.66 (m, 1.5H), 7.61 (dd, J=8.3, 7.3 Hz, 0.5H), 7.43 (ddd, J=8.3, 1.9, 0.9 Hz, 0.5H), 7.35-7.26 (m, 1H), 7.16-7.09 (m, 0.5H), 6.88 (dd, J=16.1, 7.3 Hz, 1H), 6.76 (d, J=8.4 Hz, 0.5H), 6.53 (d, J=8.3 Hz, 0.5H), 4.74-4.64 (m, 1H), 4.24-4.04 (m, 1H), 4.02-3.76 (m, 2H), 2.55-2.21 (m, 5H), 2.05-1.23 (m, 8H).

Example 19: (±)-(5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl)(2-(((5-methylpyridin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 13 substituting 2-chloro-4-(trifluoromethyl)pyrimidine with 2-chloro-5-(methyl)pyridine. MS (ESI) mass calcd. for C₂₃H₂₅N₅O₂, 403.2; m/z found 404.2 [M+H]⁺. ¹H NMR (CDCl₃): 8.10-7.58 (m, 4H), 7.43-7.29 (m, 1.5H), 7.26-7.11 (m, 1.5H), 6.66 (d, J=8.4 Hz, 0.5H), 6.45 (d, J=8.4 Hz, 0.5H), 4.86-4.71 (m, 1H), 4.17-3.66 (m, 3H), 2.46-2.38 (s, 1.2H), 2.31-2.14 (m, 3.8H), 2.01-1.79 (m, 2H), 1.71-1.18 (m, 6H).

Example 20: (±)-(2-(((3,6-dimethylpyrazin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)(5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone

Prepared analogous to Example 13 substituting 2-chloro-4-(trifluoromethyl)pyrimidine with 3-chloro-2,5-dimethylpyrazine. MS (ESI) mass calcd. for C₂₃H₂₆N₆O₂, 418.2; m/z found 419.2 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) 7.88-7.84 (m, 1H), 7.81-7.72 (m, 2.5H), 7.36-7.12 (m, 2H), 7.11-7.06 (m, 0.5H), 4.86-4.75 (m, 1H), 4.26-4.15 (m, 0.5H), 4.08 (dd, J=11.0, 5.5 Hz, 1H), 3.86-3.71 (m, 1.5H), 2.48-2.34 (m, 6H), 2.34-2.13 (m, 3H), 1.96-1.25 (m, 7H).

Example 21: (±)-(5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl)(2-(((3-(trifluoromethyl)quinoxalin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 13 substituting 2-chloro-4-(trifluoromethyl)pyrimidine with 2-chloro-3-(trifluoromethyl)quinoxaline. MS (ESI) mass calcd. for C₂₆H₂₃F₃N₆O₂, 508.2; m/z found 509.2 [M+H]⁺. ¹H NMR (CDCl₃): 8.16-8.09 (m, 1H), 7.97-7.62 (m, 6H), 7.37-7.23 (m, 1H), 7.19-7.06 (m, 1H), 4.87 (t, J=4.7 Hz, 0.5H), 4.80 (d, J=4.8 Hz, 0.5H), 4.71-4.56 (m, 0.5H), 4.38-4.22 (m, 1H), 4.16-4.01 (m, 0.5H), 3.87-3.73 (m, 1H), 2.49-2.23 (m, 4H), 2.05-1.24 (m, 6H).

Example 22: (±)-(2-(2H-1,2,3-triazol-2-yl)phenyl)(2-(((5-fluoropyridin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 7 substituting intermediate A-21 with intermediate A-1. MS (ESI) mass calcd. for C₂₁H₂₀FN₅O₂, 393.2; m/z found 394.2 [M+H]⁺. ¹H NMR (400 MHz, MeOD) 8.02-7.78 (m, 4H), 7.62-7.53 (m, 0.5H), 7.49-7.28 (m, 3H), 7.13-7.01 (m, 0.5H), 6.75 (dd, J=9.0, 3.6 Hz, 0.5H), 6.51 (dd, J=9.0, 3.6 Hz, 0.5H), 4.85-4.71 (m, 1H), 4.21-4.03 (m, 1H), 4.02-3.72 (m, 2H), 2.39-2.09 (m, 1H), 2.04-1.16 (m, 6H).

Example 23: (±)-2-(((5-fluoropyridin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)(quinolin-8-yl)methanone

Prepared analogous to Example 22 substituting intermediate A-1 with quinoline-8-carboxylic acid. MS (ESI) mass calcd. for C₂₂H₂₀FN₃O₂, 377.2; m/z found 378.2 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃): 8.95-8.69 (m, 1H), 8.16 (dd, J=8.3, 1.8 Hz, 0.4H), 8.11-7.81 (m, 2H), 7.81-7.67 (m, 1H), 7.64-7.51 (m, 1H), 7.47-7.09 (m, 2.6H), 6.79 (dd, J=9.0, 3.6 Hz, 0.5H), 6.25 (s, 0.5H), 5.08-4.96 (m, 1H), 4.29 (s, 0.7H), 4.13-3.94 (m, 1.3H), 3.65-3.45 (m, 1H), 2.47-2.02 (m, 2H), 2.02-1.30 (m, 5H).

Example 24: (±)-2-(((5-fluoropyridin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)(naphthalen-1-yl)methanone

Prepared analogous to Example 22 substituting intermediate A-1 with 1-naphthoic acid. MS (ESI) mass calcd. for C₂₃H₂₁FN₂O₂, 376.2; m/z found 377.2 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃): 8.10-7.95 (m, 1.5H), 7.92-7.83 (m, 1.5H), 7.81-7.71 (m, 1H), 7.58-7.31 (m, 4H), 7.25-7.13 (m, 1H), 6.77 (dd, J=9.0, 3.6 Hz, 0.5H), 6.36-6.24 (m, 0.5H), 5.04-4.92 (m, 1H), 4.30-4.13 (m, 1H), 4.07-3.84 (m, 1H), 3.81-3.64 (m, 1H), 2.44-2.30 (m, 0.5H), 2.27-2.00 (m, 1.5H), 1.89-1.37 (m, 5H).

Example 25: (±)-2-(((5-fluoropyridin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)(2-methylnaphthalen-1-yl)methanone

Prepared analogous to Example 22 substituting intermediate A-1 with 2-methyl-1-naphthoic acid. ¹H NMR (CDCl₃): 8.06-7.86 (m, 1H), 7.85-7.62 (m, 2.6H), 7.60-7.54 (m, 0.2H), 7.49-7.21 (m, 3.4H), 7.13 (m, 0.8H), 6.77 (ddd, J=12.7, 9.0, 3.6 Hz, 0.6H), 6.43 (dd, J=9.0, 3.6 Hz, 0.2H), 6.03 (dd, J=9.0, 3.6 Hz, 0.2H), 5.11-4.99 (m, 0.9H), 4.38-4.09 (m, 1.2H), 4.08-3.82 (m, 0.7H), 3.69-3.43 (m, 1.2H), 2.58-2.27 (m, 3.5H), 2.23-1.97 (m, 1.5H), 1.92-1.28 (m, 5H).

Example 26: (±)-2-(1H-pyrazol-1-yl)phenyl)(2-(((5-fluoropyridin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 22 substituting intermediate A-1 with 2-(1H-pyrazol-1-yl)benzoic acid. MS (ESI) mass calcd. for C₂₂H₂₁FN₄O₂, 392.2; m/z found 393.2 [M+H]⁺. ¹H NMR (CDCl₃): 7.98 (dd, J=8.3, 3.1 Hz, 1H), 7.91-7.83 (m, 1H), 7.69 (d, J=1.9 Hz, 1H), 7.64-7.23 (m, 4.5H), 6.99 (t, J=7.4 Hz, 0.5H), 6.71 (dd, J=9.0, 3.6 Hz, 0.5H), 6.47-6.34 (m, 1.5H), 4.79-4.63 (m, 1H), 4.03-3.65 (m, 2H), 3.66-3.54 (m, 1H), 2.27-2.03 (m, 1H), 1.86-0.74 (m, 6H).

Example 27: (±)-2-(((5-fluoropyridin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)(3-phenylfuran-2-yl)methanone

Prepared analogous to Example 22 substituting intermediate A-1 with 3-phenylfuran-2-carboxylic acid. MS (ESI) mass calcd. for C₂₂H₂₁FN₂O₃, 392.2; m/z found 393.2 [M+H]⁺. ¹H NMR (CDCl₃): 8.05-7.82 (m, 1H), 7.59-7.44 (m, 7H), 6.77-6.40 (m, 2H), 4.85-4.61 (m, 1H), 4.45-4.29 (m, 0.5H), 4.24-4.08 (m, 0.5H), 4.06-3.76 (m, 2H), 2.32-2.11 (m, 1H), 2.01-0.83 (m, 6H).

Example 28: (±)-(2-ethoxynaphthalen-1-yl)(2-(((5-fluoropyridin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 22 substituting intermediate A-1 with 2-ethoxy-1-naphthoic acid. MS (ESI) mass calcd. for C₂₅H₂₅FN₂O₃, 420.2; m/z found 421.2 [M+H]⁺. ¹H NMR (CDCl₃): 8.03 (d, J=3.0 Hz, 0.2H), 7.95 (dd, J=8.1, 3.1 Hz, 0.5H), 7.86-7.70 (m, 2.6H), 7.69-7.63 (m, 0.3H), 7.60-7.55 (m, 0.3H), 7.50-7.00 (m, 4.2H), 6.76 (ddd, J=9.3, 6.1, 3.6 Hz, 0.5H), 6.44 (dd, J=9.0, 3.5 Hz, 0.2H), 6.03 (dd, J=9.0, 3.6 Hz, 0.2H), 5.08-4.97 (m, 1H), 4.35-3.92 (m, 3.3H), 3.91-3.76 (m, 0.5H), 3.68-3.52 (m, 1.2H), 2.44-2.27 (m, 0.8H), 2.20-1.93 (m, 2H), 1.85-1.18 (m, 7.2H).

Example 29: (±)-(5-(2-fluorophenyl)-2-methylthiazol-4-yl)(2-(((5-fluoropyridin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 22 substituting intermediate A-1 with 5-(2-fluorophenyl)-2-methylthiazole-4-carboxylic acid. MS (ESI) mass calcd. for C₂₃H₂₁F₂N₃O₂S, 441.2; m/z found 442.2 [M+H]⁺. ¹H NMR (CDCl₃): 7.99-7.93 (m, 1H), 7.53-7.44 (m, 1H), 7.36-7.09 (m, 3.5H), 7.04 (ddd, J=9.8, 8.5, 1.2 Hz, 0.5H), 6.66 (ddd, J=15.9, 9.0, 3.6 Hz, 1H), 4.79-4.68 (m, 1H), 4.27-4.21 (m, 0.5H), 4.07 (t, J=4.6 Hz, 0.5H), 3.96-3.73 (m, 2H), 2.74 (s, 1.5H), 2.42 (s, 1.5H), 2.23-2.11 (m, 1H), 1.89-1.57 (m, 2H), 1.54-1.24 (m, 3.5H), 0.92-0.81 (m, 0.5H).

Example 30: (±)-(5-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl)(2-(((5-fluoropyridin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 22 substituting intermediate A-1 with intermediate A-10. MS (ESI) mass calcd. for C₂₁H₁₉F₂N₅O₂, 411.2; m/z found 412.2 [M+H]⁺. ¹H NMR (CDCl₃): 7.98 (dd, J=7.4, 3.0 Hz, 1H), 7.86 (ddd, J=21.7, 8.9, 4.7 Hz, 1H), 7.81-7.75 (m, 1.5H), 7.38-7.03 (m, 3.5H), 6.72 (dd, J=9.0, 3.6 Hz, 0.5H), 6.52 (dd, J=9.0, 3.6 Hz, 0.5H), 4.85-4.75 (m, 1H), 4.17-4.02 (m, 1H), 4.02-3.83 (m, 1H), 3.83-3.75 (m, 1H), 2.34-2.15 (m, 1H), 2.03-1.80 (m, 1H), 1.74-1.20 (m, 5H).

Example 31: (±)-(2-fluoro-6-(pyrimidin-2-yl)phenyl)(2-(((5-fluoropyridin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 22 substituting intermediate A-1 with intermediate A-6. MS (ESI) mass calcd. for C₂₃H₂₀F₂N₄O₂, 422.2; m/z found 423.2 [M+H]⁺. ¹H NMR (CDCl₃): 8.93-8.61 (m, 1.8H), 8.15-7.92 (m, 1.6H), 7.56-7.05 (m, 4.3H), 6.94 (t, J=8.6 Hz, 0.3H), 6.73 (ddd, J=8.9, 5.2, 3.5 Hz, 0.6H), 6.59-6.35 (m, 0.4H), 4.99-4.79 (m, 1H), 4.31 (t, J=9.9 Hz, 0.3H), 4.25-3.63 (m, 2.7H), 2.47-1.11 (m, 7H).

Example 32: (±)-(5-fluoro-2-(pyrimidin-2-yl)phenyl)(2-(((5-fluoropyridin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 22 substituting intermediate A-1 with 5-fluoro-2-(pyrimidin-2-yl)benzoic acid. MS (ESI) mass calcd. for C₂₃H₂₀F₂N₄O₂, 422.2; m/z found 423.2 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) 8.78 (d, J=4.9 Hz, 1H), 8.72 (d, J=4.8 Hz, 1H), 8.22 (ddd, J=20.6, 8.7, 5.5 Hz, 1H), 8.01-7.93 (m, 1H), 7.37-7.27 (m, 1H), 7.23-7.13 (m, 1.5H), 7.13-6.99 (m, 1.5H), 6.72 (dd, J=9.0, 3.5 Hz, 0.5H), 6.52 (dd, J=9.0, 3.5 Hz, 0.5H), 4.90-4.75 (m, 1H), 4.25-3.91 (m, 2H), 3.91-3.78 (m, 1H), 2.39-2.15 (m, 1H), 2.08-1.13 (m, 6H).

Example 33: (±)-(2-(((5-fluoropyridin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)(5-methyl-2-(pyrimidin-2-yl)phenyl)methanone

Prepared analogous to Example 22 substituting intermediate A-1 with 5-methyl-2-(pyrimidin-2-yl)benzoic acid. MS (ESI) mass calcd. for C₂₄H₂₃FN₄O₂, 418.2; m/z found 419.2 [M+H]⁺. ¹H NMR (CDCl₃): 8.81-8.68 (m, 2H), 8.09 (dd, J=9.9, 8.0 Hz, 1H), 7.98 (dd, J=8.6, 3.1 Hz, 1H), 7.41-7.24 (m, 1.5H), 7.22-7.16 (m, 1H), 7.16-7.09 (m, 1.5H), 6.73 (dd, J=9.1, 3.6 Hz, 0.5H), 6.52 (dd, J=9.0, 3.6 Hz, 0.5H), 4.88-4.77 (m, 1H), 4.21-4.01 (m, 1H), 4.01-3.89 (m, 1H), 3.88-3.76 (m, 1H), 2.42 (s, 1.6H), 2.35-2.10 (m, 1H), 2.07-1.81 (m, 2.4H), 1.81-1.16 (m, 5H).

Example 34: (±)-(2-(2H-1,2,3-triazol-2-yl)phenyl)(2-((quinoxalin-2-yloxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl methanone

Step A: (±)-2-(-7-azabicyclo[2.2.1]heptan-2-ylmethoxy)quinoxaline. To intermediate B-10 (240 mg, 1.1 mmol) in THF (4 mL) was added NaOtBu (130 mg, 1.4 mmol). The reaction was heated at reflux for 15 min and 2-chloroquinoxaline (207 mg, 1.3 mmol) was added. After 45 min, the reaction was cooled to rt and ½ saturated NH₄Cl (aq) was added. The solution was made slightly basic with 5% Na₂CO₃ (aq) and extracted with DCM (3×). The combined organics were dried (Na₂SO₄). The resulting compound was treated with TFA in DCM. After the reaction was complete, the reaction was concentrated, neutralized with 5% Na₂CO₃ and extracted with DCM. The combined organics were dried (Na₂SO₄). Purification via silica gel chromatography (1-7% (2M NH₃ in MeOH)/DCM) gave the title compound (208 mg, 78%). MS (ESI) mass calcd. for C₁₅H₁₇N₃O, 255.1; m/z found 256.2 [M+H]⁺.

Step B: (±)-(2-(2H-1,2,3-triazol-2-yl)phenyl)(2-((quinoxalin-2-yloxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)methanone. Prepared analogous to Example 7 substituting 6-methyl-3-(2H-1,2,3-triazol-2-yl)picolinic acid with intermediate A-1 and (±)-2-(((5-fluoropyridin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptane with the title compound of Step A. MS (ESI) mass calcd. for C₂₄H₂₂N₆O₂, 426.2; m/z found 427.2 [M+H]⁺. ¹H NMR (CDCl₃): 8.49 (s, 0.5H), 8.31-8.21 (s, 0.5H), 8.08-7.98 (m, 1H), 7.95-7.75 (m, 3.4H), 7.75-7.66 (m, 1.1H), 7.65-7.50 (m, 1.7H), 7.50-7.39 (m, 1.1H), 7.36-7.28 (m, 1H), 7.24-7.13 (m, 0.7H), 4.92-4.80 (m, 1H), 4.47-4.28 (m, 1H), 4.22-4.07 (m, 1H), 3.87-3.77 (m, 1H), 2.46-2.23 (m, 1.7H), 2.07-1.83 (m, 1.3H), 1.82-1.29 (m, 4H).

Example 35: (±)-(2-fluoro-6-(2H-1,2,3-triazol-2-yl)phenyl)(2-((quinoxalin-2-yloxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 34 substituting intermediate A-1 with intermediate A-11. MS (ESI) mass calcd. for C₂₄H₂₁FN₆O₂, 444.2; m/z found 445.2 [M+H]. ¹H NMR (CDCl₃): 8.52-8.47 (m, 0.5H), 8.27-8.21 (m, 0.4H), 8.07-7.95 (m, 1H), 7.91-7.09 (m, 7.8H), 6.72-6.63 (m, 0.3H), 4.98-4.87 (m, 1H), 4.63-4.54 (dd, J=10.7, 9.1 Hz, 0.5H), 4.46-4.29 (m, 1H), 4.20-4.04 (m, 0.5H), 3.96-3.76 (m, 1H), 2.51-2.23 (m, 1H), 2.17-1.88 (m, 1H), 1.84-1.19 (m, 5H).

Example 36: (±)-(5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl)(2-((quinoxalin-2-yloxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 34 substituting intermediate A-1 with intermediate A-37. MS (ESI) mass calcd. for C₂₅H₂₄N₆O₂, 440.2; m/z found 441.2 [M+H]⁺. ¹H NMR (CDCl₃): 8.49 (s, 0.5H), 8.26 (s, 0.5H), 8.03 (ddd, J=8.3, 4.4, 1.4 Hz, 1H), 7.90-7.74 (m, 3H), 7.74-7.65 (m, 1H), 7.59 (dddd, J=8.3, 7.0, 4.8, 1.4 Hz, 1H), 7.33 (ddd, J=8.3, 1.9, 0.9 Hz, 0.6H), 7.29-7.22 (m, 1H), 7.21-7.10 (m, 1.4H), 4.90-4.79 (m, 1H), 4.46-3.98 (m, 2H), 3.91-3.72 (m, 1H), 2.47-2.20 (m, 4H), 2.05-1.22 (m, 6H).

Example 37: (±)-(5-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl)(2-((quinoxalin-2-yloxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 34 substituting intermediate A-1 with intermediate A-10. MS (ESI) mass calcd. for C₂₄H₂₁FN₆O₂, 444.2; m/z found 445.2 [M+H]⁺. ¹H NMR (CDCl₃): 8.55-8.44 (m, 0.5H), 8.36-8.23 (m, 0.5H), 8.08-8.00 (m, 1H), 7.90-7.55 (m, 5H), 7.49-7.09 (m, 3H), 4.91-4.82 (m, 1H), 4.50-4.29 (m, 1H), 4.23-4.07 (m, 1H), 3.82 (dd, J=10.0, 5.0 Hz, 1H), 2.48-2.25 (m, 1H), 2.09-1.88 (m, 1H), 1.82-1.31 (m, 5H).

Example 38: (±)-(5-methyl-2-(pyrimidin-2-yl)phenyl)(2-((quinoxalin-2-yloxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 34 substituting intermediate A-1 with intermediate A-34. MS (ESI) mass calcd. for C₂₇H₂₅N₅O₂, 451.2; m/z found 452.2 [M+H]⁺. ¹H NMR (CDCl₃): 8.87-8.79 (m, 1H), 8.75-8.68 (m, 1H), 8.49 (s, 0.5H), 8.27 (s, 0.5H), 8.14-7.98 (m, 2H), 7.85 (ddd, J=16.5, 8.3, 1.5 Hz, 1H), 7.74-7.66 (m, 1H), 7.64-7.54 (m, 1H), 7.35-7.29 (m, 0.5H), 7.24-7.19 (m, 0.5H), 7.18-7.07 (m, 2H), 4.94-4.83 (m, 1H), 4.52-4.07 (m, 2H), 3.93-3.82 (m, 1H), 2.51-2.20 (m, 2.6H), 2.08-1.83 (m, 1.4H), 1.81-1.12 (m, 6H).

Example 39: (±)-(2-(((4,6-dimethylpyrimidin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)(5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone

Step A: (±)-2-(((4,6-dimethylpyrimidin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptane. Prepared analogous to Example 34 substituting 2-chloroquinoxaline with 2-chloro-4,6-dimethylpyrimidine. ¹H NMR (CDCl₃): 6.65 (s, 1H), 4.21-3.99 (m, 2H), 3.74-3.56 (m, 2H), 2.39 (s, 6H), 2.14 (ddd, J=9.0, 5.1, 3.7 Hz, 1H), 1.86 (s, 2H), 1.67-1.49 (m, 2H), 1.47-1.30 (m, 2H).

Step B: (±)-(2-(((4,6-dimethylpyrimidin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)(5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone. Prepared analogous to Example 7 substituting 6-methyl-3-(2H-1,2,3-triazol-2-yl)picolinic acid with 5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoic acid and (±)-2-(((5-fluoropyridin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptane with the title compound of Step A. MS (ESI) mass calcd. for C₂₃H₂₆N₆O₂, 418.2; m/z found 419.2 [M+H]⁺. ¹H NMR (CDCl₃): 7.83-7.70 (m, 2.5H), 7.35-7.10 (m, 2.5H), 6.71-6.65 (m, 1H), 4.87-4.72 (m, 1H), 4.34 (dd, J=10.5, 8.8 Hz, 0.5H), 4.14-3.89 (m, 2H), 3.79-3.70 (m, 0.5H), 2.48-2.18 (m, 7.5H), 2.07-1.83 (m, 2.5H), 1.79-1.18 (m, 6H).

Example 40: (±)-2-(((4,6-dimethylpyrimidin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)(3-methyl-5-phenylisoxazol-4-yl)methanone

Prepared analogous to Example 39 substituting 5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoic acid with 3-methyl-5-phenylisoxazole-4-carboxylic acid. MS (ESI) mass calcd. for C₂₄H₂₆N₄O₃, 418.2; m/z found 419.2 [M+H]⁺. ¹H NMR (CDCl₃): 7.67 (m, 2H), 7.50-7.31 (m, 3H), 6.69 (d, J=6.7 Hz, 1H), 4.74 (dd, J=10.8, 5.1 Hz, 1H), 4.17 (dd, J=10.8, 9.2 Hz, 0.5H), 3.85-3.78 (m, 1H), 3.70 (d, J=4.9 Hz, 0.5H), 3.64-3.42 (m, 1H), 2.55 (s, 1.4H), 2.49 (s, 1.6H), 2.43 (s, 3H), 2.39 (s, 3H), 2.29-2.07 (m, 1H), 1.90-1.55 (m, 2H), 1.53-1.06 (m, 3H), 0.76-0.53 (m, 1H).

Example 41: (±)-(2-(((4,6-dimethylpyrimidin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)(2-ethoxynaphthalen-1-yl)methanone

Prepared analogous to Example 39 substituting 5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoic acid with 2-ethoxy-1-naphthoic acid. ¹H NMR (CDCl₃): 7.91-7.70 (m, 2.5H), 7.67-7.54 (m, 0.5H), 7.49-7.38 (m, 0.8H), 7.37-7.28 (m, 0.8H), 7.27-7.16 (m, 0.9H), 7.10-7.02 (m, 0.5H), 6.70 (s, 0.2H), 6.65 (s, 0.5H), 6.53 (s, 0.3H), 5.09-4.95 (m, 1H), 4.56-4.47 (m, 0.5H), 4.28-3.87 (m, 3.3H), 3.79-3.55 (m, 1.2H), 2.46-2.35 (m, 4.5H), 2.28 (s, 1.5H), 2.21-1.95 (m, 2H), 1.85-1.51 (m, 3.5H), 1.51-1.24 (m, 4.5H).

Example 42: (±)-(2-(((4,6-dimethylpyrimidin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)(2-ethoxyphenyl)methanone)

Prepared analogous to Example 39 substituting 5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoic acid with 2-ethoxybenzoic acid. MS (ESI) mass calcd. for C₂₂H₂₇N₃O₃, 381.2; m/z found 382.2 [M+H]⁺. ¹H NMR (CDCl₃): 7.34-7.27 (m, 1H), 7.21-7.12 (m, 1H), 6.98-6.92 (m, 0.5H), 6.89 (d, J=8.2 Hz, 0.5H), 6.78 (d, J=8.3 Hz, 0.5H), 6.72-6.63 (m, 1.5H), 4.89-4.78 (m, 1H), 4.36 (dd, J=10.6, 8.7 Hz, 0.5H), 4.14-3.71 (m, 4.5H), 2.45-2.16 (m, 6.5H), 2.06-1.82 (m, 1.5H), 1.82-1.28 (m, 8H).

Example 43: (±)-(2-(((4,6-dimethylpyrimidin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)(2-fluoro-6-(pyrimidin-2-yl)phenyl)methanone

Prepared analogous to Example 39 substituting 5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoic acid with 2-fluoro-6-(pyrimidin-2-yl)benzoic acid. MS (ESI) mass calcd. for C₂₄H₂₄FN₅O₂, 433.2; m/z found 434.2 [M+H]⁺. ¹H NMR (CDCl₃): 9.02-8.90 (m, 0.7H), 8.82-8.65 (m, 1.3H), 8.14-7.95 (m, 1H), 7.58-7.31 (m, 1H), 7.31-7.07 (m, 1.7H), 6.97-6.86 (m, 0.3H), 6.75-6.51 (m, 1H), 4.96-4.83 (m, 1H), 4.55 (dd, J=10.3, 9.0 Hz, 0.25H), 4.36 (dd, J=10.6, 8.9 Hz, 0.25H), 4.21-3.78 (m, 2.5H), 2.48-1.17 (m, 13H).

Example 44: (±)-(2-(((4,6-dimethylpyrimidin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)(5-fluoro-2-(pyrimidin-2-yl)phenyl)methanone

Prepared analogous to Example 39 substituting 5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoic acid with 5-fluoro-2-(pyrimidin-2-yl)benzoic acid. MS (ESI) mass calcd. for C₂₄H₂₄FN₅O₂, 433.2; m/z found 434.2 [M+H]⁺. ¹H NMR (CDCl₃): 8.88-8.78 (m, 1H), 8.72 (d, J=4.8 Hz, 1H), 8.26 (dd, J=8.7, 5.5 Hz, 0.5H), 8.22-8.16 (m, 0.5H), 7.29-7.09 (m, 2H), 7.06-6.97 (m, 1H), 6.68 (s, 1H), 4.88-4.81 (m, 1H), 4.40 (t, J=9.7 Hz, 0.5H), 4.25 (t, J=10.8 Hz, 0.5H), 4.05 (dd, J=10.2, 6.2 Hz, 0.5H), 3.99-3.91 (m, 1H), 3.89-3.80 (m, 0.5H), 2.45-2.21 (m, 7H), 2.05-1.87 (m, 1H), 1.81-1.30 (m, 5H).

Example 45: (±)-(2-(((4,6-dimethylpyrimidin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)(5-methyl-2-(pyrimidin-2-yl)phenyl)methanone

Prepared analogous to Example 39 substituting 5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoic acid with 5-methyl-2-(pyrimidin-2-yl)benzoic acid. MS (ESI) mass calcd. for C₂₅H₂₇N₅O₂, 429.2; m/z found 430.2 [M+H]⁺. ¹H NMR (CDCl₃): 8.83 (d, J=5.0 Hz, 1H), 8.71 (d, J=4.8 Hz, 1H), 8.09 (dd, J=13.6, 8.0 Hz, 1H), 7.33-7.10 (m, 3H), 6.68 (d, J=1.4 Hz, 1H), 4.90-4.79 (m, 1H), 4.41 (dd, J=10.4, 8.8 Hz, 0.5H), 4.20 (t, J=10.6 Hz, 0.5H), 4.07-3.94 (m, 1.5H), 3.80 (t, J=4.7 Hz, 0.5H), 2.49-2.19 (m, 7H), 2.04-1.89 (m, 3H), 1.87-1.47 (m, 4.5H), 1.45-1.29 (m, 1.5H).

Example 46: (±)-(2-(((4,6-dimethylpyrimidin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)(2-(thiophen-2-yl)phenyl)methanone

Prepared analogous to Example 11 substituting (±)-2-(((5-fluoropyridin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptane with (±)-2-(((4,6-dimethylpyrimidin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptane. MS (ESI) mass calcd. for C₂₄H₂₅N₃O₂S, 419.2; m/z found 420.2 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃): 7.55-6.83 (m, 7H), 6.75-6.62 (m, 1H), 4.87-4.62 (m, 1H), 4.09-3.38 (m, 3H), 2.54-2.32 (m, 6H), 2.32-2.03 (m, 1H), 1.97-0.87 (m, 6H).

Example 47: (±)-(6-methyl-3-(2H-1,2,3-triazol-2-yl)pyridin-2-yl)(2-(((5-(trifluoromethyl)pyridin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Step A: (±)-2-(((5-(trifluoromethyl)pyridin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptane. Prepared analogous to Example 49 substituting 5-bromo-2-fluoropyridine with 2-fluoro-5-(trifluoromethyl)pyridine. MS (ESI) mass calcd. for C₁₃H₁₅F₃N₂O, 272.1; m/z found 273.1, [M+H]⁺.

Step B: (±)-(6-methyl-3-(2H-1,2,3-triazol-2-yl)pyridin-2-yl)(2-(((5-(trifluoromethyl)pyridin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)methanone. Prepared analogous to Example 1 substituting 5-fluoro-2-(pyrimidin-2-yl)benzoic acid with 6-methyl-3-(2H-1,2,3-triazol-2-yl)picolinic acid and (1S,2R,4R)-tert-butyl-2-((pyridin-2-yloxy)methyl)-7-azabicyclo[2.2.1]heptane-7-carboxylate with the title compound of Step A. MS (ESI) mass calcd. for C₂₂H₂₁F₃N₆O₂, 458.2; m/z found 459.2 [M+H]⁺. ¹H NMR (CDCl₃): 8.47-8.37 (m, 1H), 8.12 (dd, J=13.2, 8.4 Hz, 1H), 7.85-7.69 (m, 3H), 7.32 (dd, J=8.4, 0.6 Hz, 0.5H), 7.22 (dd, J=8.4, 0.6 Hz, 0.5H), 6.88-6.82 (m, 0.5H), 6.69-6.59 (m, 0.5H), 4.93-4.81 (m, 1H), 4.39-4.18 (m, 2H), 3.94-3.87 (m, 1H), 2.65-2.60 (s, 1.2H), 2.39-2.22 (m, 2.8H), 2.11-1.33 (m, 6H).

Example 48: (±)-(3-ethoxy-6-methylpyridin-2-yl)(2-(((5-(trifluoromethyl)pyridin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 47 substituting 6-methyl-3-(2H-1,2,3-triazol-2-yl)picolinic acid with 3-ethoxy-6-methylpicolinic acid. MS (ESI) mass calcd. for C₂₂H₂₄F₃N₃O₃, 435.2; m/z found 436.2 [M+H]⁺. ¹H NMR (CDCl₃): 8.43-8.35 (m, 1H), 7.79-7.68 (m, 1H), 7.18-7.07 (m, 1H), 7.07-6.96 (m, 1H), 6.86 (d, J=8.7 Hz, 0.5H), 6.64 (d, J=8.7 Hz, 0.5H), 4.92-4.86 (m, 1H), 4.29-4.20 (m, 1H), 4.19-4.10 (m, 1H), 4.10-3.83 (m, 2H), 3.74 (t, J=3.9 Hz, 1H), 2.52-2.47 (s, 1.5H), 2.41-2.32 (m, 0.5H), 2.28-2.18 (m, 2H), 2.07-1.84 (m, 2H), 1.78-1.63 (m, 1H), 1.62-1.41 (m, 3H), 1.37 (dt, J=11.8, 7.0 Hz, 3H).

Example 49: (±)-(2-(((5-bromopyridin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)(6-methyl-3-(2H-1,2,3-triazol-2-yl)pyridin-2-yl)methanone

Step A: (±)-2-(((5-bromopyridin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptane. To intermediate B-10 (175 mg, 0.8 mmol) in DMF (3.5 mL) at 0° C. was added NaH (60 wt % in mineral oil, 37 mg, 0.9 mmol). After 30 min, 5-bromo-2-fluoropyridine (190 mg, 1.1 mmol) in DMF (0.5 mL) was added dropwise and the 0° C. ice bath was removed. After 2 h, brine was added and the reaction extracted with EtOAc (2×). The combined organics were washed with brine and dried (Na₂SO₄) to give a clear oil which was treated with TFA and DCM (1:1, 10 mL). After 2 h, the reaction was concentrated, dissolved in DCM and neutralized with 5% Na₂CO₃ (aq). The combined organics were extracted with DCM (3×) and dried (Na₂SO₄) to give the title compound that was used in subsequent reactions without further purification. MS (ESI) mass calcd. for C₁₂H₁₅BrN₂O, 282.0; m/z found 283.1, 285.1 [M+H]⁺. NMR (500 MHz, CDCl₃): 8.17 (d, J=2.5 Hz, 1H), 7.63 (dd, J=8.8, 2.5 Hz, 1H), 6.65 (d, J=8.8 Hz, 1H), 4.08-3.99 (m, 2H), 3.65 (t, J=4.5 Hz, 1H), 3.59 (d, J=4.1 Hz, 1H), 2.12-2.06 (m, 1H), 1.87 (s, 1H), 1.68-1.52 (m, 2H), 1.45-1.13 (m, 3H), 0.95-0.76 (m, 1H).

Step B: Prepared analogous to Example 1 substituting 5-fluoro-2-(pyrimidin-2-yl)benzoic acid with 6-methyl-3-(2H-1,2,3-triazol-2-yl)picolinic acid and (1S,2R,4R)-tert-butyl-2-((pyridin-2-yloxy)methyl)-7-azabicyclo[2.2.1]heptane-7-carboxylate with the title compound of Step A. MS (ESI) mass calcd. for C₂₁H₂₁BrN₆O₂, 468.1; m/z found 469.1, 471.1 [M+H]⁺. ¹H NMR (CDCl₃): 8.20 (d, J=2.6 Hz, 0.4H), 8.16 (d, J=2.6 Hz, 0.6H), 8.13 (d, J=8.3 Hz, 0.4H), 8.10 (d, J=8.4 Hz, 0.6H), 7.82-7.77 (m, 2H), 7.64 (dd, J=8.8, 2.6 Hz, 0.4H), 7.60 (dd, J=8.8, 2.6 Hz, 0.6H), 7.33-7.29 (m, 0.4H), 7.22 (d, J=8.4 Hz, 0.6H), 6.69 (d, J=8.8 Hz, 0.4H), 6.50 (d, J=8.8 Hz, 0.6H), 4.84 (dd, J=11.1, 5.2 Hz, 1H), 4.30-4.04 (m, 2H), 3.93-3.85 (m, 1H), 2.62 (s, 1.3H), 2.38-2.17 (m, 2.7H), 2.11-1.95 (m, 1H), 1.94-1.77 (m, 1H), 1.77-1.40 (m, 4H).

Example 50: (±)-(2-(((5-bromopyridin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)(3-fluoro-2-methoxyphenyl)methanone

Prepared analogous to Example 49 substituting 6-methyl-3-(2H-1,2,3-triazol-2-yl)picolinic acid with 3-fluoro-2-methoxybenzoic acid. MS (ESI) mass calcd. for C₂₀H₂₀BrFN₂O₃, 434.1; m/z found 435.1, 437.1 [M+H]⁺. ¹H NMR (CDCl₃): 8.19-8.12 (m, 1H), 7.61 (ddd, J=26.6, 8.8, 2.5 Hz, 1H), 7.16-6.98 (m, 2H), 6.96 (dt, J=7.6, 1.3 Hz, 0.5H), 6.85-6.81 (m, 0.5H), 6.69 (dd, J=8.8, 0.8 Hz, 0.5H), 6.46 (d, J=8.7 Hz, 0.5H), 4.88-4.77 (m, 1H), 4.17-4.06 (m, 1H), 4.03-3.86 (m, 4H), 3.81-3.75 (m, 1H), 2.37-2.22 (m, 1H), 2.04-1.40 (m, 6H).

Example 51: (±)-(2-(((5-bromopyridin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)(3-ethoxy-6-methylpyridin-2-yl)methanone

Prepared analogous to Example 49 substituting 6-methyl-3-(2H-1,2,3-triazol-2-yl)picolinic acid with 3-ethoxy-6-methylpicolinic acid. MS (ESI) mass calcd. for C₂₁H₂₄BrN₃O₃, 445.1; m/z found 446.1, 448.1 [M+H]⁺. ¹H NMR (CDCl₃): 8.17-8.11 (m, 1H), 7.61 (ddd, J=19.5, 8.8, 2.6 Hz, 1H), 7.16-7.06 (m, 1H), 7.05-6.96 (m, 1H), 6.69 (dd, J=8.8, 0.7 Hz, 0.5H), 6.47 (dd, J=8.8, 0.7 Hz, 0.5H), 4.90-4.84 (m, 1H), 4.20-4.10 (m, 1H), 4.09-3.82 (m, 3H), 3.78-3.72 (m, 1H), 2.50 (s, 1.4H), 2.38-2.25 (m, 2.6H), 2.04-1.84 (m, 2H), 1.75-1.40 (m, 4H), 1.60-1.40 (m, 3H), 1.36 (dt, J=7.8, 7.0 Hz, 3H).

Example 52: (±)-(3-fluoro-2-(pyrimidin-2-yl)phenyl)(2-((pyridin-2-yloxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 1 substituting 5-fluoro-2-(pyrimidin-2-yl)benzoic acid with 3-fluoro-2-(pyrimidin-2-yl)benzoic acid and intermediate B-9 with intermediate B-10. MS (ESI) mass calcd. for C₂₃H₂₁FN₄O₂, 404.2; m/z found 405.2 [M+H]⁺. ¹H NMR (CDCl₃): 8.81 (dd, J=18.0, 4.9 Hz, 2H), 8.20-8.12 (m, 1H), 7.56 (ddd, J=8.3, 7.1, 2.0 Hz, 1H), 7.45 (td, J=8.0, 5.1 Hz, 0.5H), 7.28-7.22 (m, 1.5H), 7.21-7.08 (m, 1.5H), 7.05-6.96 (m, 0.5H), 6.88 (dddd, J=13.2, 7.1, 5.1, 1.0 Hz, 1H), 6.71 (dt, J=8.4, 0.9 Hz, 0.5H), 6.61 (dt, J=8.4, 0.9 Hz, 0.5H), 4.70-4.61 (m, 1H), 4.15-4.07 (m, 1H), 4.06-3.89 (m, 2H), 2.26 (ddt, J=15.3, 8.3, 4.5 Hz, 1H), 1.93-1.27 (m, 6H).

Example 53: (±)-(6-methyl-3-(2H-1,2,3-triazol-2-yl)pyridin-2-yl)(2-((pyridazin-3-yloxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Step A: (±)-tert-butyl 2-((pyridazin-3-yloxy)methyl)-7-azabicyclo[2.2.1]heptane-7-carboxylate. To intermediate B-10 (266 mg, 1.2 mmol) in THF (4 mL) at 0 C was added NaH (60 wt % in mineral oil, 70 mg, 1.8 mmol). After 15 min, 3-chloropyridazine (160 mg, 1.4 mmol) was added. The reaction allowed to warm to rt. After 18 h, H₂O was added and the mixture extracted with EtOAc. The organic layer was dried. Purification via silica gel chromatography (0-30% EtOAc in heptane) gave the title compound (300 mg, 90%). MS (ESI) mass calcd. for C₁₆H₂₃N₃O₃, 305.2; m/z found 306.0 [M+H]⁺.

Step B: (±)-2-((pyridazin-3-yloxy)methyl)-7-azabicyclo[2.2.1]heptane hydrochloride. To the title compound from step A (300 mg, 1 mmol) in 1,4-dioxane (3 mL) was added 6N HCl in iPrOH (1 mL). The reaction was heated to 70° C. for 3 h, cooled to rt and concentrated to give the title compound that was used without further purification. MS (ESI) mass calcd. for C₁₁H₁₅N₃O, 205.1; m/z found 206.0 [M+H]⁺.

Step C: (±)-(6-methyl-3-(2H-1,2,3-triazol-2-yl)pyridin-2-yl)(2-((pyridazin-3-yloxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)methanone. To 6-methyl-3-(2H-1,2,3-triazol-2-yl)picolinic acid (270 mg, 1.3 mmol) in DMF (3 mL) was added DIPEA (630 μL, 3.6 mmol), HBTU (590 mg, 1.5 mmol) and the title compound from step B (250 mg, 1 mmol). After stirring overnight, saturated NaHCO₃ (aq) was added and the mixture extracted with EtOAc (3×). The combined organics were dried (MgSO₄). Purification by reverse phase chromatography gave material that was triturated with Et₂O/pentane to give the title compound (115 mg, 28%) as a beige solid. MS (ESI) mass calcd. for C₂₀H₂₁N₇O₂, 391.2; m/z found 392.2 [M+H]⁺. ¹H NMR (DMSO-D₆): 8.91 (dd, J=8.5, 4.4 Hz, 1H), 8.23-8.04 (m, 3H), 7.69-7.52 (m, 1.5H), 7.41 (d, J=8.4 Hz, 0.5H), 7.28 (d, J=8.9 Hz, 0.5H), 7.10 (d, J=8.9 Hz, 0.5H), 4.60 (t, J=4.8 Hz, 1H), 4.40-4.19 (m, 2H), 3.87 (t, J=4.3 Hz, 0.5H), 3.79 (d, J=4.3 Hz, 0.5H), 2.58 (s, 1.5H), 2.46-2.24 (m, 1H), 2.06 (s, 1.5H), 1.81-1.34 (m, 6H).

Example 54: (±)-(6-methyl-3-(2H-1,2,3-triazol-2-yl)pyridin-2-yl)(2-(((2-methylpyridin-3-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Step A: (±)-tert-butyl-2-(((methylsulfonyl)oxy)methyl)-7-azabicyclo[2.2.1]heptane-7-carboxylate. To intermediate B-10 (545 mg, 2.4 mmol) in DCM (12 mL) at 0° C. was added TEA (333 μL, 2.4 mmol) followed by MsCl (190 μL, 2.4 mmol). After 2 h, brine was added and the mixture was extracted with DCM (2×). The combined organics were dried (Na₂SO₄) to give the title compound (650 mg, 89%) that was used without further purification. MS (ESI) mass calcd. for C₁₂H₂₃NO₅S, 305.1; m/z found 249.9 [M−55]⁺.

Step B: (±)-tert-butyl 2-(((2-methylpyridin-3-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptane-7-carboxylate. To 2-methylpyridin-3-ol in DMF was added KOH. The solution was stirred for 30 min at rt, then the title compound from step A was added and the reaction was heated at 80° C. After 5 h, H₂O was added and the mixture extracted with EtOAc. The combined organic layers were dried (MgSO₄). Purification via silica gel chromatography (0-7% MeOH in DCM) gave the title compound (201 mg, 90%). MS (ESI) mass calcd. for C₁₈H₂₆N₂O₃, 318.2; m/z found 319.0 [M+1]⁺.

Step C: (±)-2-(((2-methylpyridin-3-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptane. Prepared analogous to example 53 step B substituting (±)-tert-butyl 2-((pyridazin-3-yloxy)methyl)-7-azabicyclo[2.2.1]heptane-7-carboxylate with (±)-tert-butyl 2-(((2-methylpyridin-3-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptane-7-carboxylate. MS (ESI) mass calcd. for C₁₃H₁₈N₂O, 218.1; m/z found 219.1 [M+1]⁺.

Step D: (±)-(6-methyl-3-(2H-1,2,3-triazol-2-yl)pyridin-2-yl)(2-(((2-methylpyridin-3-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)methanone.

Prepared analogous to example 53 step C substituting (±)-2-((pyridazin-3-yloxy)methyl)-7-azabicyclo[2.2.1]heptane hydrochloride with (±)-2-(((2-methylpyridin-3-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptane. MS (ESI) mass calcd. for C₂₂H₂₄N₆O₂, 404.2; m/z found 405.2 [M+H]⁺. ¹H NMR (DMSO-D₆): 8.22-7.92 (m, 4H), 7.55 (d, J=8.4 Hz, 0.3H), 7.45-7.33 (m, 1H), 7.32-7.10 (m, 1.7H), 4.60-4.57 (m, 1H), 3.92-3.67 (m, 3H), 2.57 (s, 0.9H), 2.42-2.18 (m, 1.9H), 2.08 (s, 2.1H), 1.95 (s, 2.1H), 1.80-1.31 (m, 6H).

Example 55: (±)-(6-methyl-3-(2H-1,2,3-triazol-2-yl)pyridin-2-yl)(2-(((3-methylpyridin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Step A: (±)-tert-butyl 2-(((2-methylpyridin-3-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptane-7-carboxylate. Prepared analogous to Example 7 Step A Method A substituting PBu₃ with PPh₃, DEAD with DIAD, 5-fluoropyridin-2(1H)-one with 3-methylpyridin-2-ol and performing the reaction at rt. MS (ESI) mass calcd. for C₁₈H₂₆N₂O₃, 318.2; m/z found 319.0 [M+H]⁺.

Step B: (±)-2-(((2-methylpyridin-3-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptane. Prepared analogous to Example 53 Step B substituting (±)-tert-butyl 2-((pyridazin-3-yloxy)methyl)-7-azabicyclo[2.2.1]heptane-7-carboxylate with (±)-tert-butyl 2-(((2-methylpyridin-3-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptane-7-carboxylate. MS (ESI) mass calcd. for C₁₃H₁₈N₂O, 218.1; m/z found 219.0 [M+H]⁺.

Step C: (±)-(6-methyl-3-(2H-1,2,3-triazol-2-yl)pyridin-2-yl)(2-(((3-methylpyridin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)methanone.

Prepared analogous to Example 53 Step C substituting (±)-2-((pyridazin-3-yloxy)methyl)-7-azabicyclo[2.2.1]heptane hydrochloride with (±)-2-(((2-methylpyridin-3-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptane. MS (ESI) mass calcd. for C₂₂H₂₄N₆O₂, 404.2; m/z found 405.2 [M+H]⁺.

Example 56: (±)-(2-(((1-methyl-1H-pyrazol-5-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)(6-methyl-3-(2H-1,2,3-triazol-2-yl)pyridin-2-yl)methanone

Step A: (±)-tert-butyl 2-(((1-methyl-1H-pyrazol-5-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptane-7-carboxylate. Prepared analogous to Example 7 Step A Method A substituting THF with PhCH₃ and 5-fluoropyridin-2(1H)-one with 1-methyl-1H-pyrazol-5-ol. MS (ESI) mass calcd. for C₁₆H₂₅N₃O₃, 307.2; m/z found 308.0 [M+H]⁺.

Step B: (±)-2-(((1-methyl-1H-pyrazol-5-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptane. Prepared analogous to Example 53 Step B substituting (±)-tert-butyl 2-((pyridazin-3-yloxy)methyl)-7-azabicyclo[2.2.1]heptane-7-carboxylate the title compound of Step A. MS (ESI) mass calcd. for C₁₁H₁₇N₃O, 207.1; m/z found 208.0 [M+H]⁺.

Step C: (±)-(2-(((1-methyl-1H-pyrazol-5-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)(6-methyl-3-(2H-1,2,3-triazol-2-yl)pyridin-2-yl)methanone. Prepared analogous to Example 53 Step C substituting (±)-2-((pyridazin-3-yloxy)methyl)-7-azabicyclo[2.2.1]heptane hydrochloride with the title compound of Step B. MS (ESI) mass calcd. for C₂₀H₂₃N₇O₂, 393.2; m/z found 394.2 [M+H]⁺. ¹H NMR (DMSO-D₆): 8.18-8.05 (m, 3H), 7.56 (d, J=8.4 Hz, 0.4H), 7.49 (d, J=8.4 Hz, 0.6H), 7.23 (d, J=1.7 Hz, 0.4H), 7.19 (d, J=1.7 Hz, 0.6H), 5.70 (d, J=1.8 Hz, 0.4H), 5.59 (d, J=1.8 Hz, 0.6H), 4.59-4.56 (m, 1H), 3.96-3.76 (m, 3H), 3.57 (s, 1.2H), 3.34 (s, 1.8H), 2.58 (s, 1.2H), 2.39-2.17 (m, 2.8H), 1.87-1.27 (m, 6H).

Example 57: (±)-(6-methyl-3-(2H-1,2,3-triazol-2-yl)pyridin-2-yl)(2-((pyridin-4-yloxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 54 substituting 2-methylpyridin-3-ol with pyridin-4-ol. MS (ESI) mass calcd. for C₂₁H₂₂N₆O₂, 390.2; m/z found 391.2 [M+H]⁺. ¹H NMR (DMSO-D₆): 8.41 (d, J=5.5 Hz, 0.8H), 8.36 (d, J=5.5 Hz, 1.2H), 8.20-8.02 (m, 3H), 7.55 (d, J=8.4 Hz, 0.4H), 7.40 (d, J=8.4 Hz, 0.6H), 7.00 (d, J=6.2 Hz, 0.8H), 6.88 (d, J=6.2 Hz, 1.2H), 4.64-4.51 (m, 1H), 4.02-3.78 (m, 2.4H), 3.75 (d, J=4.4 Hz, 0.6H), 2.57 (s, 1.2H), 2.39-2.20 (m, 1H), 2.04 (s, 1.8H), 1.87-1.30 (m, 6H).

Example 58: # (±)-(6-methyl-3-(2H-1,2,3-triazol-2-yl)pyridin-2-yl)(2-((pyridin-3-yloxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 54 substituting 2-methylpyridin-3-ol with pyridin-3-ol. MS (ESI) mass calcd. for C₂₁H₂₂N₆O₂, 390.2; m/z found 391.2 [M+H]⁺. ¹H NMR (DMSO-D₆): 8.33 (d, J=2.7 Hz, 0.4H), 8.21-8.05 (m, 4.6H), 7.55 (d, J=8.4 Hz, 0.4H), 7.46-7.25 (m, 2.6H), 4.58 (t, J=4.8 Hz, 1H), 3.95-3.80 (m, 2.4H), 3.77 (d, J=4.4 Hz, 0.6H), 2.57 (s, 1.2H), 2.38-2.18 (m, 1H), 2.02 (s, 1.8H), 1.85-1.31 (m, 6H).

Example 59: (±)-(6-methyl-3-(2H-1,2,3-triazol-2-yl)pyridin-2-yl)(2-((pyrimidin-2-yloxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 53 substituting 2-chloropyridazine with 2-chloropyrimidine. MS (ESI) mass calcd. for C₂₀H₂₁N₇O₂, 391.2; m/z found 392.2 [M+H]⁺. ¹H NMR (DMSO-D₆): 8.65 (d, J=4.8 Hz, 0.8H), 8.59 (d, J=4.8 Hz, 1.2H), 8.22-8.02 (m, 3H), 7.56 (d, J=8.4 Hz, 0.4H), 7.44 (d, J=8.4 Hz, 0.6H), 7.19-7.13 (m, 1H), 4.59 (t, J=4.5 Hz, 0.6H), 4.55 (d, J=4.4 Hz, 0.4H), 4.24-4.04 (m, 2H), 3.85 (t, J=4.3 Hz, 0.4H), 3.78 (d, J=4.0 Hz, 0.6H), 2.58 (s, 1.2H), 2.39-2.21 (m, 1H), 2.11 (s, 1.8H), 1.86-1.29 (m, 6H).

Example 60: (±)-(6-methyl-3-(2H-1,2,3-triazol-2-yl)pyridin-2-yl)(2-((pyrazin-2-yloxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 53 substituting 2-chloropyridazine with 2-pyrazine. MS (ESI) mass calcd. for C₂₀H₂₁N₇O₂, 391.2; m/z found 392.2 [M+H]⁺.

Example 61: (±)-(6-methyl-3-(2H-1,2,3-triazol-2-yl)pyridin-2-yl)(2-((pyrimidin-4-yloxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 55 substituting 3-methylpyridin-2-ol with pyrimidin-4-ol. MS (ESI) mass calcd. for C₂₀H₂₁N₇O₂, 391.2; m/z found 392.2 [M+H]⁺. The product is present as a mixture of conformers (ratio ca. 50:50) ¹H NMR (300 MHz, DMSO) 8.84 (s, 0.5H), 8.77 (s, 0.5H), 8.53 (d, J=5.8 Hz, 0.5H), 8.49 (d, J=5.8 Hz, 0.5H), 8.22-8.01 (m, 3H), 7.55 (d, J=8.4 Hz, 0.5H), 7.43 (d, J=8.4 Hz, 0.5H), 7.00 (d, J=5.7 Hz, 0.5H), 6.85 (d, J=5.8 Hz, 0.5H), 4.58 (t, J=3.7 Hz, 0.5H), 4.53 (d, J=4.2 Hz, 0.5H), 4.25-4.04 (m, 2H), 3.85 (t, J=3.7 Hz, 0.5H), 3.75 (d, J=3.9 Hz, 0.5H), 2.57 (s, 1.5H), 2.40-2.16 (m, 1H), 2.12 (s, 1.5H), 1.85-1.31 (m, 6H).

Example 62: (±)-(6-methyl-3-(2H-1,2,3-triazol-2-yl)pyridin-2-yl)(2-(((6-methylpyridin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 55 substituting 3-methylpyridin-2-ol with 6-methylpyridin-2-ol. MS (ESI) mass calcd. for C₂₂H₂₄N₆O₂, 404.2; m/z found 405.2 [M+H]⁺. ¹H NMR (DMSO-D₆): 8.17 (d, J=8.4 Hz, 0.5H), 8.12 (d, J=8.4 Hz, 0.5H), 8.10 (s, 1H), 8.06 (s, 1H), 7.63-7.49 (m, 1.5H), 7.41 (d, J=8.4 Hz, 0.5H), 6.85 (d, J=7.2 Hz, 0.5H), 6.81 (d, J=7.2 Hz, 0.5H), 6.64 (d, J=8.2 Hz, 0.5H), 6.46 (d, J=8.2 Hz, 0.5H), 4.58 (t, J=4.4 Hz, 0.5H), 4.54 (d, J=4.5 Hz, 0.5H), 4.16-3.95 (m, 2H), 3.83 (t, J=4.4 Hz, 0.5H), 3.74 (d, J=4.4 Hz, 0.5H), 2.58 (s, 1.5H), 2.43 (s, 1.5H), 2.37 (s, 1.5H), 2.33-2.14 (m, 1H), 2.11 (s, 1.5H), 1.85-1.31 (m, 6H).

Example 63: (±)-(2-(((5-fluoropyridin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)(6-methyl-3-(oxazol-2-yl)pyridin-2-yl)methanone

Prepared analogous to Example 7 substituting intermediate A-21 with intermediate A-43. MS (ESI) mass calcd. for C₂₂H₂₁FN₄O₃, 408.2; m/z found 409.2 [M+H].

Example 64: (±)-(2-(((5-fluoropyridin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)(6-methyl-3-(pyrimidin-2-yl)pyridin-2-yl)methanone

Prepared analogous to Example 7 substituting intermediate A-21 with 6-methyl-3-(pyrimidin-2-yl)picolinic acid. MS (ESI) mass calcd. for C₂₃H₂₂FN₅O₂, 419.2; m/z found 420.2 [M+H]⁺. ¹H NMR (DMSO-D₆): 8.91 (d, J=4.9 Hz, 0.8H), 8.84 (d, J=4.9 Hz, 1.2H), 8.33-8.29 (m, 1H), 8.22 (d, J=3.1 Hz, 0.4H), 8.13 (d, J=3.1 Hz, 0.6H), 7.76-7.59 (m, 1H), 7.53-7.41 (m, 1.4H), 7.35 (d, J=8.1 Hz, 0.6H), 6.94 (dd, J=9.1, 3.6 Hz, 0.4H), 6.75 (dd, J=9.1, 3.6 Hz, 0.6H), 4.59 (t, J=4.1 Hz, 0.6H), 4.56 (d, J=3.8 Hz, 0.4H), 4.16 (dd, J=14.6, 6.2 Hz, 1H), 4.08-3.97 (m, 1H), 3.87 (br s, 0.4H), 3.76 (d, J=3.9 Hz, 0.6H), 2.56 (s, 1.2H), 2.39-2.15 (m, 1H), 2.10 (s, 1.8H), 1.91-1.32 (m, 6H).

Example 65: (±)-(3,6′-dimethyl-[2,3′-bipyridin]-2′-yl)(2-(((5-fluoropyridin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 7 substituting intermediate A-21 with 3,6′-dimethyl-[2,3′-bipyridine]-2′-carboxylic acid. MS (ESI) mass calcd. for C₂₅H₂₅FN₄O₂, 432.2; m/z found 433.2 [M+H]⁺. ¹H NMR (DMSO-D₆): 8.33 (t, J=5.1 Hz, 1H), 8.16 (s, 1H), 7.79-7.60 (m, 3H), 7.40 (d, J=7.9 Hz, 0.5H), 7.32-7.23 (m, 1H), 7.20 (dd, J=7.6, 4.8 Hz, 0.5H), 6.85 (dd, J=9.1, 3.6 Hz, 0.5H), 6.80 (dd, J=9.1, 3.6 Hz, 0.5H), 4.39 (brs, 0.5H), 4.35 (d, J=4.1 Hz, 0.5H), 4.19 (t, J=10.3 Hz, 0.5H), 4.04 (dd, J=10.4, 5.2 Hz, 0.5H), 3.90 (d, J=4.8 Hz, 0.5H), 3.85 (t, J=4.0 Hz, 0.5H), 3.75-3.53 (m, 1H), 2.56 (s, 1.5H), 2.22 2.17 (m, 3.5H), 2.11 (s, 1.5H), 1.90-1.81 (m, 0.5H), 1.79-1.17 (m, 6H).

Example 66: (±)-(2-(((5-fluoropyridin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)(6-methyl-3-(3-methyl-1,2,4-oxadiazol-5-yl)pyridin-2-yl)methanone

Prepared analogous to Example 7 substituting intermediate A-21 with 6-methyl-3-(3-methyl-1,2,4-oxadiazol-5-yl)picolinic acid. MS (ESI) mass calcd. for C₂₂H₂₂FN₅O₃, 423.2; m/z found 424.2 [M+H]⁺. ¹H NMR (DMSO-D₆): 8.33 (d, J=8.1 Hz, 0.4H), 8.28 (d, J=8.1 Hz, 0.6H), 8.14 (d, J=3.1 Hz, 0.4H), 8.10 (d, J=3.1 Hz, 0.6H), 7.76-7.60 (m, 1H), 7.58 (d, J=8.2 Hz, 0.4H), 7.47 (d, J=8.2 Hz, 0.6H), 6.95 (dd, J=3.6, 9.2 Hz, 0.4H), 6.72 (dd, J=3.6, 9.2 Hz, 0.6H), 4.67 (t, J=4.5 Hz, 0.6H), 4.62 (d, J=4.6 Hz, 0.4H), 4.16-3.92 (m, 2H), 3.81 (t, J=4.3 Hz, 0.4H), 3.73 (d, J=4.6 Hz, 0.6H), 2.60 (s, 1.2H), 2.41 (s, 1.2H), 2.38 (s, 1.8H), 2.37-2.19 (m, 1H), 2.18 (s, 1.8H), 1.90-1.30 (m, 6H).

Example 67: (±)-(2-(((5-fluoropyridin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)(6-methyl-3-(3-methyl-1H-pyrazol-1-yl)pyridin-2-yl)methanone

Prepared analogous to Example 7 substituting intermediate A-21 with 6-methyl-3-(3-methyl-1H-pyrazol-1-yl)picolinic acid. MS (ESI) mass calcd. for C₂₃H₂₄FN₅O₂, 421.2; m/z found 422.2 [M+H]⁺. MP=123.2° C.

Example 68: (±)-(2-(((5-fluoropyridin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)(6-methyl-3-(pyrrolidin-1-yl)pyridin-2-yl)methanone

Step A: 6-methyl-3-(pyrrolidin-1-yl)picolinonitrile. To 2-bromo-6-methyl-3-(2H-1,2,3-triazol-2-yl)pyridine (720 mg, 3.7 mmol), pyrrolidine (450 μL, 5.5 mmol), Pd(OAc)₂ (25 mg, 11 mol %), XPhos (122 mg, 25 mol %) and Cs₂CO₃ (2.4 g, 7.3 mmol) in a sealed tube was added PhCH₃. The vessel was sealed and heated at 100° C. overnight. After cooling to rt, the reaction was diluted with EtOAc and H₂O. The organic layer was dried (MgSO₄) and concentrated. Purification via silica gel chromatography (0-50% EtOAc in DCM) gave the title compound (186 mg, 27%).

Step B: 6-methyl-3-(pyrrolidin-1-yl)picolinic acid. To the title compound of Step A (162 mg, 0.9 mmol) in EtOH (2.6 mL) was added 4M KOH (650 μL, 2.6 mmol). The reaction was then heated at 90° C. for 18 h. Additional 4M KOH (1.5 mL, 6 mmol) was added and heating continued overnight. The reaction was then cooled to rt, acidified with 1N HCl (aq), concentrated and used without further purification in the next step.

Step C: (±)-(2-(((5-fluoropyridin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)(6-methyl-3-(pyrrolidin-1-yl)pyridin-2-yl)methanone Prepared analogous to Example 7 substituting intermediate A-9 with the title compound from Step B. MS (ESI) mass calcd. for C₂₃H₂₇FN₄O₂, 410.2; m/z found 411.2 [M+H]⁺. ¹H NMR (DMSO-D₆): 8.14 (d, J=3.0 Hz, 0.5H), 8.10 (d, J=3.0 Hz, 0.5H), 7.68-7.38 (m, 2H), 6.92 (dd, J=9.1, 3.6 Hz, 0.5H), 6.71 (dd, J=9.1, 3.6 Hz, 0.5H), 4.66 (br s, 0.5H), 4.60 (br s, 0.5H), 4.08-3.01 (m, 7H), 2.45 (s, 1.5H), 2.40-2.01 (m, 2.5H), 1.94-1.30 (m, 10H).

Example 69: # (±)-(2-(((5-fluoropyridin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)(6-methyl-3-(3-methylisoxazol-5-yl)pyridin-2-yl)methanone

Prepared analogous to Example 7 substituting intermediate A-21 with 6-methyl-3-(3-methylisoxazol-5-yl)picolinic acid. MS (ESI) mass calcd. for C₂₃H₂₃FN₄O₃, 422.2; m/z found 423.2 [M+H]⁺. ¹H NMR (DMSO-D₆): 8.11 (dt, J=10.0, 5.4 Hz, 2H), 7.77-7.55 (m, 1H), 7.50 (d, J=8.2 Hz, 0.4H), 7.38 (d, J=8.2 Hz, 0.6H), 6.94 (dd, J=9.1, 3.6 Hz, 0.4H), 6.70 (dd, J=9.1, 3.6 Hz, 0.6H), 6.62 (d, J=1.6 Hz, 1H), 4.67 (t, J=4.6 Hz, 0.6H), 4.61 (d, J=4.7 Hz, 0.4H), 3.98-3.88 (m, 2H), 3.60 (t, J=4.5 Hz, 0.4H), 3.54 (d, J=3.8 Hz, 0.6H), 2.55 (s, 1.2H), 2.38-2.14 (m, 4H), 2.12 (s, 1.8H), 1.86-1.13 (m, 6H).

Example 70: (±)-(2-(((5-fluoropyridin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)(6-methyl-3-(1H-pyrazol-1-yl)pyridin-2-yl)methanone

Prepared analogous to Example 63 substituting 6-methyl-3-(oxazol-2-yl)picolinic acid with 6-methyl-3-(1H-pyrazol-1-yl)picolinic acid. MS (ESI) mass calcd. for C₂₂H₂₂FN₅O₂, 407.2; m/z found 408.2 [M+H]⁺. ¹H NMR (DMSO-D₆): 8.17 (d, J=3.1 Hz, 0.5H), 8.13 (d, J=3.1 Hz, 0.5H), 8.08 (t, J=2.4 Hz, 1H), 7.95 (t, J=8.5 Hz, 1H), 7.74-7.61 (m, 2H), 7.49 (d, J=8.3 Hz, 0.5H), 7.36 (d, J=8.4 Hz, 0.5H), 6.91 (dd, J=9.1, 3.6 Hz, 0.5H), 6.72 (dd, J=9.1, 3.6 Hz, 0.5H), 6.52-6.49 (m, 0.5H), 6.49-6.46 (m, 0.5H), 4.55 (t, J=4.5 Hz, 0.5H), 4.50 (d, J=4.7 Hz, 0.5H), 3.94 (d, J=7.6 Hz, 2H), 3.67 (t, J=4.2 Hz, 0.5H), 3.59 (d, J=4.5 Hz, 0.5H), 2.54 (s, 1.5H), 2.30-2.11 (m, 1H), 2.07 (s, 1.5H), 1.76-1.14 (m, 6H).

Example 71: (±)-(5-methyl-3-(2H-1,2,3-triazol-2-yl)pyridin-2-yl)(2-((pyridin-2-yloxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 2 substituting intermediate A-9 with 5-methyl-3-(2H-1,2,3-triazol-2-yl)picolinic acid. MS (ESI) mass calcd. for C₂₁H₂₂N₆O₂, 390.2; m/z found 391.0 [M+H]⁺. MP=159.7° C.

Example 72: (±)-(4-methyl-3-(2H-1,2,3-triazol-2-yl)pyridin-2-yl)(2-((pyridin-2-yloxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 2 substituting intermediate A-9 with 4-methyl-3-(2H-1,2,3-triazol-2-yl)picolinic acid. MS (ESI) mass calcd. for C₂₁H₂₂N₆O₂, 390.2; m/z found 391.0 [M+H]⁺. MP=114.5° C.

Example 73: (±)-(3-(dimethylamino)-6-methylpyridin-2-yl)(2-((pyridin-2-yloxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Step A: 3-(dimethylamino)-6-methylpicolinamide. A mixture of 3-bromo-6-methylpicolinonitrile (1 g, 5 mmol) and dimethylamine (2 mL) were heated in a microwave reactor for 2 h at 140° C. The mixture was then concentrated and purified via silica gel chromatography (0-5% MeOH in DCM) to give the title compound (249 mg, 27%). MS (ESI) mass calcd. for C₉H₁₃N₃O, 179.1; m/z found 180.0 [M+H].

Step B: 3-(dimethylamino)-6-methylpicolinic acid. To the title compound of Step A (91 mg, 0.5 mmol) in EtOH (1 mL) was added 4M KOH (0.5 μL). The reaction was then heated at 90° C. for 18 h. The reaction was then cooled to rt, acidified with 1N HCl (aq) to pH=3, concentrated and used without further purification in the next step.

Step C: Prepared analogous to Example 2 substituting intermediate A-9 with the title compound of Step B. MS (ESI) mass calcd. for C₂₁H₂₆N₄O₂, 366.2; m/z found 367 [M+H]⁺.

Example 74: (±)-(3-(2H-1,2,3-triazol-2-yl)quinolin-2-yl)(2-((pyridin-2-yloxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 2 substituting intermediate A-9 with 3-(2H-1,2,3-triazol-2-yl)quinoline-2-carboxylic acid. MS (ESI) mass calcd. for C₂₄H₂₂N₆O₂, 426.2; m/z found 427.2 [M+H]⁺. ¹H NMR (DMSO-D₆): 8.93 (s, 0.5H), 8.87 (s, 0.5H), 8.26-8.09 (m, 2H), 7.96-7.86 (m, 0.5H), 7.82-7.51 (m, 5H), 7.33 (d, J=8.4 Hz, 0.5H), 7.00 (t, J=6.0 Hz, 1H), 6.87 (d, J=8.3 Hz, 0.5H), 6.52 (d, J=8.3 Hz, 0.5H), 4.70-4.57 (m, 1H), 4.33 (t, J=10.5 Hz, 0.5H), 4.24-4.05 (m, 1.5H), 4.00 (br t, J=3.8 Hz, 0.5H), 3.93 (d, J=3.6 Hz, 0.5H), 2.44-2.20 (m, 1H), 2.01-1.35 (m, 6H).

Example 75: (±)-(7-ethoxyquinolin-8-yl)(2-((pyridin-2-yloxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 2 substituting intermediate A-9 with intermediate A-29. MS (ESI) mass calcd. for C₂₄H₂₅N₃O₃, 403.2; m/z found 404.2 [M+H]⁺. ¹H NMR (DMSO-D₆): 9.02-8.54 (m, 1.6H), 8.42 (d, J=7.9 Hz, 0.8H), 8.31-7.83 (m, 2.2H), 7.83-6.75 (m, 3.8H), 6.64-6.46 (m, 0.2H), 6.24 (m, 0.4H), 4.86-4.62 (m, 1.2H), 4.46-4.01 (m, 3.6H), 3.61-3.23 (m, 1.2H), 2.44-2.06 (m, 1H), 2.06-1.15 (m, 9H).

Example 76: (±)-(3,6-dimethylimidazo[1,2-a]pyridin-5-yl)(2-((pyridin-2-yloxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Step A: 3,6-dimethylimidazo[1,2-a]pyridine-5-carboxylic acid. Prepared analogous to Example 82 substituting chloroacetaldehyde with 2-bromopropanal. MS (ESI) mass calcd. for C₁₀H₁₀N₂O₂, 190.1; m/z found 191.0 [M+H]⁺.

Step B: (±)-(3,6-dimethylimidazo[1,2-a]pyridin-5-yl)(2-((pyridin-2-yloxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)methanone. Prepared analogous to Example 2 substituting intermediate A-9 with the title compound of Step A. MS (ESI) mass calcd. for C₂₂H₂₄N₄O₂, 376.2; m/z found 377.2 [M+H]⁺. The product is present as a mixture of conformers (ratio ca. 85:15). ¹H NMR (300 MHz, DMSO) 8.18 (dd, J=4.5, 1.4 Hz, 0.85H), 7.91 (d, J=5.1 Hz, 0.15H), 7.74 (td, J=7.1, 1.8 Hz, 0.85H), 7.53 (d, J=9.1 Hz, 0.85H), 7.50-7.39 (m, 0.15H), 7.36 (s, 1H), 7.12 (dd, J=6.3 Hz, 1H), 7.06-6.95 (m, 0.85H), 6.88 (d, J=8.4 Hz, 0.85H), 6.72 (d, J=8.6 Hz, 0.15H), 6.62 (d, J=7.4 Hz, 0.15H), 6.46 (d, J=8.5 Hz, 0.15H), 4.77 (d, J=4.4 Hz, 0.85H), 4.72 (d, J=3.6 Hz, 0.15H), 4.25-4.10 (m, 1H), 4.10-3.98 (m, 1H), 3.78 (br s, 0.85H), 3.69 (br s, 0.15H), 2.48-2.38 (m, 1.85H), 2.36 (s, 2H), 2.30 (s, 2H), 2.25-2.21 (m, 0.85H), 2.20-2.16 (m, 0.3H), 1.98-1.32 (m, 6H).

Example 77: (±)-(1-methyl-4-phenyl-1H-pyrazol-3-yl)(2-((pyridin-2-yloxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 2 substituting intermediate A-9 with 1-methyl-4-phenyl-1H-pyrazole-3-carboxylic acid. MS (ESI) mass calcd. for C₂₃H₂₄N₄O₂, 388.2; m/z found 389.2 [M+H]⁺. ¹H NMR (DMSO-D₆): 8.18 (d, J=3.8 Hz, 0.5H), 8.08 (d, J=3.9 Hz, 0.5H), 8.03 (s, 0.5H), 7.92 (s, 0.5H), 7.76-7.62 (m, 1H), 7.46-7.16 (m, 5H), 7.04-6.90 (m, 1H), 6.84 (d, J=8.3 Hz, 0.5H), 6.71 (d, J=8.3 Hz, 0.5H), 4.60 (t, J=4.6 Hz, 0.5H), 4.56 (d, J=4.7 Hz, 0.5H), 4.15 (br s, 1H), 4.06 (br s, 1H), 3.98-3.83 (m, 2.5H), 3.55 (s, 1.5H), 2.29-2.15 (m, 1H), 1.79-1.22 (m, 6H).

Example 78: (±)-(1-methyl-3-phenyl-1H-pyrazol-4-yl)(2-((pyridin-2-yloxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 2 substituting intermediate A-9 with 1-methyl-3-phenyl-1H-pyrazole-4-carboxylic acid. MS (ESI) mass calcd. for C₂₃H₂₄N₄O₂, 388.2; m/z found 389.2 [M+H]⁺. ¹H NMR (DMSO-D₆): 8.16 (br s, 1H), 8.09-7.75 (m, 1H), 7.70 (t, J=7.2 Hz, 1H), 7.58 (d, J=7.0 Hz, 2H), 7.47-7.20 (m, 3H), 7.10-6.90 (m, 1H), 6.92-6.52 (br s, 1H), 4.48 (br s, 1H), 4.21-3.44 (m, 6H), 2.17 (br s, 1H), 1.86-1.05 (m, 6H).

Example 79: (±)-((3,7-dimethylimidazo[1,2-a]pyridin-8-yl)(2-((pyridin-2-yloxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Step A: Prepared analogous to Example 76 substituting 6-amino-3-methylpicolinic acid with 2-amino-4-methylnicotinic acid.

Step B: (±)-((3,7-dimethylimidazo[1,2-a]pyridin-8-yl)(2-((pyridin-2-yloxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)methanone. Prepared analogous to Example 2 substituting intermediate A-9 with 3,7-dimethylimidazo[1,2-a]pyridine-8-carboxylic acid. MS (ESI) mass calcd. for C₂₂H₂₄N₄O₂, 376.2; m/z found 377.2 [M+H]⁺. ¹H NMR (DMSO-D₆): 8.24-8.03 (m, 2H), 7.80-7.68 (m, 0.5H), 7.61 (br s, 0.5H), 7.30 (s, 1H), 7.06-6.27 (m, 3H), 4.70 (t, J=4.3 Hz, 1H), 4.32-3.67 (m, 2H), 3.42 (m, 2H), 2.45 (s, 2H), 2.38-2.02 (m, 4H), 2.02-1.18 (m, 6H).

Example 80: (±)-(7-methylimidazo[1,2-a]pyridin-8-yl)(2-((pyridin-2-yloxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Step A: 7-methylimidazo[1,2-a]pyridine-8-carboxylic acid. Prepared analogous to Example 82 substituting 6-amino-3-methylpicolinic acid with 2-amino-4-methylnicotinic acid.

Step B: (±)-(7-methylimidazo[1,2-a]pyridin-8-yl)(2-((pyridin-2-yloxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)methanone Prepared analogous to Example 2 substituting intermediate A-9 with the title compound of Step A. MS (ESI) mass calcd. for C₂₁H₂₂N₄O₂, 362.2; m/z found 363.2 [M+H]⁺. ¹H NMR (DMSO-D₆): 8.46 (d, J=6.9 Hz, 0.5H), 8.38 (d, J=6.3 Hz, 0.5H), 8.17 (d, J=3.6 Hz, 0.5H), 8.12 (d, J=3.8 Hz, 0.5H), 7.91 (s, 1H), 7.79-7.39 (m, 2H), 7.14-6.70 (m, 2H), 6.70-6.33 (m, 1H), 4.71 (br s, 1H), 4.45-3.66 (m, 2H), 3.63-3.22 (m, 2H), 2.44-2.02 (m, 3H), 2.02-1.08 (m, 6H).

Example 81: (±)-(1-methyl-4-phenyl-1H-pyrazol-5-yl)(2-((pyridin-2-yloxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 2 substituting intermediate A-9 with 1-methyl-4-phenyl-1H-pyrazole-5-carboxylic acid. MS (ESI) mass calcd. for C₂₃H₂₄N₄O₂, 388.2; m/z found 389.2 [M+H]⁺. ¹H NMR (DMSO-D₆): 8.19 (d, J=3.8 Hz, 0.6H), 8.09 (d, J=4.0 Hz, 0.4H), 7.79-7.57 (m, 2H), 7.43-7.19 (m, 5H), 7.05-6.91 (m, 1H), 6.84 (d, J=8.3 Hz, 0.6H), 6.62 (d, J=8.3 Hz, 0.4H), 4.62 (t, J=4.5 Hz, 0.4H), 4.57 (d, J=4.5 Hz, 0.6H), 3.96-3.87 (m, 2H), 3.85 (s, 1.8H), 3.79 (s, 1.2H), 3.58 (t, J=4.3 Hz, 0.6H), 3.52 (d, J=4.7 Hz, 0.4H), 2.28-2.02 (m, 1H), 1.76-1.07 (m, 6H).

Example 82: (±)-((6-methylimidazo[1,2-a]pyridin-5-yl)(2-((pyridin-2-yloxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Step A: 6-amino-3-methylpicolinic acid. To methyl 6-amino-3-bromopicolinate (500 mg, 2.2 mmol), tetramethylstannane (900 μL, 6.5 mmol) and LiCl (354 mg, 8.7 mmol) in DMF (6 mL) was added Pd(PPh₃)₄ (76 mg, 10 mol %). The reaction mixture was heated at 110° C. for 3 h. Additional tetramethylstannane, LiCl and Pd(PPh₃)₄ were added and heating continued for 6 h. Purification via silica gel chromatography (0-20% MeOH in DCM) gave the title compound.

Step B: 6-methylimidazo[1,2-a]pyridine-5-carboxylic acid. To the title compound of Step A (340 mg, 2.2 mmol) in H₂O (7 mL) was added 1M aq. NaOH (2.2 mL, 2.2 mmol) and chloroacetaldehyde (210 μL, 3.4 mmol) and the reaction mixture heated in a microwave reactor at 150° C. for 2 h. Additional 1M aq. NaOH (2.2 mL, 2.2 mmol) and chloroacetaldehyde (210 μL, 3.4 mmol) were added and heating continued at 150° C. for 2 h. The reaction was purified via prep HPLC to give the title compound (282 mg, 72%). MS (ESI) mass calcd. for C₉H₈N₂O₂, 176.1; m/z found 177.0 [M+H]⁺.

Step C: (±)-((6-methylimidazo[1,2-a]pyridin-5-yl)(2-((pyridin-2-yloxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)methanone. Prepared analogous to Example 2 substituting intermediate A-9 with 6-methylimidazo[1,2-a]pyridine-5-carboxylic acid. The product is present as a mixture of conformers (ratio ca. 80:20) ¹H NMR (300 MHz, DMSO) 8.44-8.13 (m, 1.6H), 8.13-7.86 (m, 3H), 7.86-7.41 (m, 1.2H), 6.97 (br d, J=33.5 Hz, 1.6H), 6.68 (br d, J=1.0 Hz, 0.2H), 6.39 (br d, J=1.0 Hz, 0.4H), 4.80 (d, J=16.5 Hz, 1.6H), 4.09-4.06 (m, 0.2H), 3.58 (s, 2H), 3.46-3.30 (m, 0.2H), 2.47-2.07 (m, 4H), 2.07-1.02 (m, 6H).

Example 83: (±)-(3-ethoxyisoquinolin-4-yl)(2-((pyridin-2-yloxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 164 substituting intermediate B-9 with intermediate B-10. MS (ESI) mass calcd. for C₂₄H₂₅N₃O₃, 403.2; m/z found 404.2 [M+H]⁺.

Example 84: (±)-(1-methyl-5-phenyl-1H-pyrazol-4-yl)(-2-((pyridin-2-yloxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 2 substituting intermediate A-9 with intermediate A-51. MS (ESI) mass calcd. for C₂₃H₂₄N₄O₂, 388.2; m/z found 389.2 [M+H]⁺.

Example 85: (±)-(6-methyl-3-(4-methylpiperazin-1-yl)pyridin-2-yl)(2-((pyridin-2-yloxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Step A: 6-methyl-3-(4-methylpiperazin-1-yl)picolinonitrile. Prepared analogous to Example 68 substituting pyrrolidine with 1-methylpiperazine. MS (ESI) mass calcd. for C₁₂H₁₆N4, 216.1; m/z found 217.0 [M+H]⁺.

Step B: 6-methyl-3-(4-methylpiperazin-1-yl)picolinic acid. Prepared analogous to Example 68 substituting 6-methyl-3-(pyrrolidin-1-yl)picolinonitrile with the title compound of Step A. MS (ESI) mass calcd. for C₁₂H₁₇N₃O₂, 235.1; m/z found 236.0 [M+H]⁺.

Step C: Prepared analogous to Example 2 substituting intermediate A-9 with the title compound of Step B. MS (ESI) mass calcd. for C₂₄H₃₁N₅O₂, 421.2; m/z found 422.2 [M+H]⁺. ¹H NMR (DMSO-D₆): 8.19-8.14 (m, 0.5H), 8.12 (dd, J=5.0, 1.5 Hz, 0.5H), 7.78-7.68 (m, 0.5H), 7.68-7.59 (m, 0.5H), 7.52 (d, J=8.4 Hz, 0.5H), 7.37 (d, J=8.4 Hz, 0.5H), 7.23 (d, J=8.4 Hz, 0.5H), 7.07 (d, J=8.3 Hz, 0.5H), 6.97 (ddd, J=12.3, 6.7, 5.4 Hz, 1H), 6.87 (d, J=8.3 Hz, 0.5H), 6.59 (d, J=8.3 Hz, 0.5H), 4.63 (t, J=4.5 Hz, 0.5H), 4.59 (d, J=3.9 Hz, 0.5H), 4.19-3.81 (m, 2H), 3.46 (t, J=3.9 Hz, 0.5H), 3.39 (d, J=4.7 Hz, 0.5H), 3.07-2.92 (m, 2H), 2.92-2.78 (m, 2H), 2.46-2.27 (m, 6H), 2.22-2.05 (m, 3.5H), 1.97 (s, 1.5H), 1.94-1.27 (m, 6H).

Example 86: (±)-(6-methyl-3-(piperazin-1-yl)pyridin-2-yl)(2-((pyridin-2-yloxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Step A: tert-butyl 4-(2-cyano-6-methylpyridin-3-yl)piperazine-1-carboxylate. Prepared analogous to Example 68 substituting pyrrolidine with tert-butyl piperazine-1-carboxylate. MS (ESI) mass calcd. for C₁₆H₂₂N₄O₂, 302.2; m/z found 303.0 [M+H]⁺.

Step B: 3-(4-(tert-butoxycarbonyl)piperazin-1-yl)-6-methylpicolinic acid.

Prepared analogous to Example 68 substituting 6-methyl-3-(pyrrolidin-1-yl)picolinonitrile with the title compound of Step A. MS (ESI) mass calcd. for C₁₆H₂₃N₃O₄, 321.2; m/z found 322.0 [M+H]⁺.

Step C: tert-butyl 4-(6-methyl-2-((±)-2-((pyridin-2-yloxy)methyl)-7-azabicyclo[2.2.1]heptane-7-carbonyl)pyridin-3-yl)piperazine-1-carboxylate. Prepared analogous to example 2 substituting intermediate A-9 with the title compound of Step B.

Step D: (±)-(6-methyl-3-(piperazin-1-yl)pyridin-2-yl)(2-((pyridin-2-yloxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)methanone. To the title compound from step C (182 mg, 0.4 mmol) in 1,4-dioxane (1 mL) was added 6N HCl in iPrOH (400 μL). The reaction was heated to 70° C. for 3 h, cooled to rt, concentrated and purified via reverse phase chromatography. The mixture was dissolved with a saturated NaHCO3 (aq) and extracted with DCM (×3). The organic layers were dried over MgSO4 and concentrated. The crude product was triturated with diethyl ether and n-pentane to give the title compound (5 mg, 3%). MS (ESI) mass calcd. for C₂₃H₂₉N₅O₂, 407.2; m/z found 408.2 [M+H]⁺. ¹H NMR (DMSO-D₆): 8.17 (d, J=4.0 Hz, 0.4H), 8.12 (d, J=3.8 Hz, 0.6H), 7.72 (t, J=7.6 Hz, 0.4H), 7.63 (t, J=6.9 Hz, 0.6H), 7.48 (d, J=8.3 Hz, 0.4H), 7.34 (d, J=8.3 Hz, 0.6H), 7.22 (d, J=8.3 Hz, 0.4H), 7.06 (d, J=8.3 Hz, 0.6H), 7.02-6.90 (m, 1H), 6.86 (d, J=8.1 Hz, 0.4H), 6.58 (d, J=8.3 Hz, 0.6H), 4.63-4.60 (m, 1H), 4.14-3.92 (m, 2H), 3.86 (t, J=10.4 Hz, 1H), 2.99-2.65 (m, 8H), 2.39 (s, 1H), 2.34-2.28 (m, 1H), 2.18-2.11 (m, 1H), 1.96-1.88 (m, 2H), 1.86-1.20 (m, 6H).

Example 87: (±)-(6-methyl-3-morpholinopyridin-2-yl)((1S,2R,4R)-2-((pyridin-2-yloxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Step A: 6-methyl-3-morpholinopicolinonitrile. Prepared analogous to Example 68 substituting pyrrolidine with morpholine. MS (ESI) mass calcd. for C₁₁H₁₃N₃O, 203.1; m/z found 204.0 [M+H]⁺.

Step B: 6-methyl-3-morpholinopicolinic acid. Prepared analogous to Example 68 substituting 6-methyl-3-(pyrrolidin-1-yl)picolinonitrile with the title compound of Step A. MS (ESI) mass calcd. for C₁₁H₁₄N₂O₃, 222.1; m/z found 223.0 [M+H]⁺.

Step C: Prepared analogous to Example 2 substituting intermediate A-9 with the title compound of Step B. MS (ESI) mass calcd. for C₂₃H₂₈N₄O₃, 408.2; m/z found 409.2 [M+H]⁺.

Example 88: (±)-(7-methoxyquinolin-8-yl)(2-((pyridin-2-yloxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Step A: 7-methoxyquinoline-8-carboxylic acid. In 1 g separate batches a mixture of 2-amino-6-methoxybenzoic acid (1 g, 66 mmol) and acrolein (4.8 mL, 72 mmol) in 1,4-dioxane (66 mL) was heated in a microwave reactor for 20 min at 200° C. After combining the reactions, the mixture was concentrated and purified via silica gel chromatography (0-10% MeOH in DCM) to give the title compound (2.8 g, 20%). MS (ESI) mass calcd. for C₁₁H₁₉NO₃, 203.1; m/z found 204.0 [M+H]⁺.

Step B: Prepared analogous to Example 2 substituting intermediate A-9 with the title compound of Step A. MS (ESI) mass calcd. for C₂₃H₂₃N₃O₃, 389.2; m/z found 390.2 [M+H]⁺.

Example 89: (±)-(2-ethoxynaphthalen-1-yl)(2-((pyridin-2-yloxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 2 substituting intermediate A-9 with 2-ethoxy-1-naphthoic acid. MS (ESI) mass calcd. for C₂₅H₂₆N₂O₃, 402.2; m/z found 403.2 [M+H]⁺.

Example 90: (±)-(3,6′-dimethyl-[2,3′-bipyridin]-2′-yl)(2-((pyridin-2-yloxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 2 substituting intermediate A-9 with 3,6′-dimethyl-[2,3′-bipyridine]-2′-carboxylic acid. MS (ESI) mass calcd. for C₂₅H₂₆N₄O₂, 414.2; m/z found 415.2 [M+H]⁺.

Example 91: (±)-(3-(2H-1,2,3-triazol-2-yl)pyridin-2-yl)(2-((pyridin-2-yloxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 2 substituting intermediate A-9 with 3-(2H-1,2,3-triazol-2-yl)picolinic acid. MS (ESI) mass calcd. for C₂₀H₂₀N₆O₂, 376.2; m/z found 377.2 [M+H]⁺. ¹H NMR (DMSO-D₆): 8.70 (d, J=3.6 Hz, 0.5H), 8.40-7.99 (m, 4.5H), 7.82-7.47 (m, 2H), 7.02-6.85 (m, 1H), 6.86 (d, J=8.2 Hz, 0.6H), 6.64 (d, J=8.1 Hz, 0.4H), 4.62-4.65 (m, 1H), 4.20-3.97 (m, 3H), 2.35-2.24 (m, 1H), 2.00-1.09 (m, 6H).

Example 92: (±)-(2-methyl-5-phenylthiazol-4-yl)(2-((pyridin-2-yloxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 2 substituting intermediate A-9 with 2-methyl-5-phenylthiazole-4-carboxylic acid. MS (ESI) mass calcd. for C₂₃H₂₃N₃O₂S, 405.2; m/z found 406.2 [M+H]⁺. ¹H NMR (DMSO-D₆) 8.18 (dd, J=5.0, 1.4 Hz, 0.5H), 8.10 (dd, J=5.0, 1.4 Hz, 0.5H), 7.77-7.61 (m, 1H), 7.52-7.29 (m, 5H), 7.04-6.89 (m, 1H), 6.82 (d, J=8.3 Hz, 0.5H), 6.69 (d, J=8.3 Hz, 0.5H), 4.57 (t, J=4.5 Hz, 0.5H), 4.52 (d, J=4.7 Hz, 0.5H), 3.90-3.79 (m, 2.5H), 3.69 (t, J=10.6 Hz, 0.5H), 2.69 (s, 1.5H), 2.28 (s, 1.5H), 2.25-2.06 (m, 1H), 1.72-1.04 (m, 6H).

Example 93: (±)-(6-methyl-3-(oxazol-2-yl)pyridin-2-yl)(2-((pyridin-2-yloxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 2 substituting intermediate A-9 with intermediate A-43. MS (ESI) mass calcd. for C₂₂H₂₂N₄O₃, 390.2; m/z found 391.2 [M+H]⁺. ¹H NMR (DMSO-D₆): 8.22 (dt, J=14.0, 7.8 Hz, 2.5H), 8.12 (dd, J=5.0, 1.4 Hz, 0.5H), 7.78-7.68 (m, 0.5H), 7.68-7.59 (m, 0.5H), 7.49 (d, J=8.2 Hz, 0.5H), 7.41-7.29 (n, 1.5H), 6.97 (ddd, J=14.7, 6.5, 5.2 Hz, 1H), 6.87 (d, J=8.4 Hz, 0.5H), 6.63 (d, J=8.3 Hz, 0.5H), 4.66 (t, J=4.6 Hz, 0.5H), 4.62 (d, J=4.8 Hz, 0.5H), 4.22-3.93 (m, 2H), 3.70 (t, J=4.4 Hz, 0.5H), 3.61 (d, J=4.0 Hz, 0.5H), 2.55 (s, 1.5H), 2.40-2.14 (m, 1H), 2.08 (s, 1.5H), 1.93-1.23 (m, 6H).

Example 94: (±)-(6-methyl-3-(3-methylisoxazol-5-yl)pyridin-2-yl)(2-((pyridin-2-yloxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 2 substituting intermediate A-9 with 6-methyl-3-(3-methylisoxazol-5-yl)picolinic acid. MS (ESI) mass calcd. for C₂₃H₂₄N₄O₃, 404.2; m/z found 405.0 [M+H]⁺. ¹H NMR (DMSO-D₆): 8.20-8.02 (m, 2H), 7.73 (t, J=6.9 Hz, 0.4H), 7.65 (t, J=7.7 Hz, 0.6H), 7.50 (d, J=8.1 Hz, 0.4H), 7.37 (d, J=8.2 Hz, 0.6H), 7.03-6.91 (m, 1H), 6.87 (d, J=8.3 Hz, 0.4H), 6.68-6.58 (m, 1.6H), 4.68 (t, J=4.6 Hz, 0.6H), 4.62 (d, J=4.7 Hz, 0.4H), 4.01-3.93 (m, 2H), 3.60 (t, J=4.4, 0.4H), 3.55 (d, J=3.1, 0.6H), 2.55 (s, 1.2H), 2.36-2.14 (m, 4H), 2.09 (s, 1.8H), 1.88-1.07 (m, 6H).

Example 95: (±)-(6-methyl-3-(1H-pyrazol-1-yl)pyridin-2-yl)(2-((pyridin-2-yloxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 2 substituting intermediate A-9 with 6-methyl-3-(1H-pyrazol-1-yl)picolinic acid. ¹H NMR (DMSO-D₆): 8.19 (dd, J=5.0, 1.4 Hz, 0.5H), 8.14 (dd, J=5.1, 1.5 Hz, 0.5H), 8.08 (t, J=2.9 Hz, 1H), 7.97 (d, J=8.3 Hz, 0.5H), 7.93 (d, J=8.3 Hz, 0.5H), 7.76-7.61 (m, 2H), 7.49 (d, J=8.4 Hz, 0.5H), 7.34 (d, J=8.4 Hz, 0.5H), 6.97 (td, J=7.3, 5.2 Hz, 1H), 6.84 (d, J=8.3 Hz, 0.5H), 6.65 (d, J=8.3 Hz, 0.5H), 6.53-6.48 (m, 0.5H), 6.48-6.43 (m, 0.5H), 4.55 (t, J=4.5 Hz, 0.5H), 4.51 (d, J=4.7 Hz, 0.5H), 4.02-3.93 (m, 2H), 3.67 (t, J=4.1 Hz, 0.5H), 3.60 (d, J=4.5 Hz, 0.5H), 2.54 (s, 1.5H), 2.31-2.11 (m, 1H), 2.04 (s, 1.5H), 1.75-1.16 (m, 6H).

Example 96: (±)-(6-methyl-3-(4-methyl-1H-pyrazol-1-yl)pyridin-2-yl)(2-((pyridin-2-yloxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 2 substituting intermediate A-9 with 6-methyl-3-(4-methyl-1H-pyrazol-1-yl)picolinic acid. MS (ESI) mass calcd. for C₂₃H₂₅N₅O₂, 403.2; m/z found 404.2 [M+H]⁺.

Example 97: (±)-(6-methyl-3-(pyrrolidin-1-yl)pyridin-2-yl)(2-((pyridin-2-yloxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 2 substituting intermediate A-9 with 6-methyl-3-(pyrrolidin-1-yl)picolinic acid (Example 68). MS (ESI) mass calcd. for C₂₃H₂₈N₄O₂, 392.2; m/z found 393.2 [M+H]⁺. The product is present as a mixture of conformers (ratio ca. 50:50). ¹H NMR (300 MHz, DMSO) 8.14 (dd, J=5.1, 1.4 Hz, 0.5H), 8.11 (dd, J=5.1, 1.4 Hz, 0.5H), 7.76-7.59 (m, 1H), 7.06 (q, J=8.6 Hz, 1H), 7.01-6.90 (m, 2H), 6.85 (d, J=8.3 Hz, 0.5H), 6.69 (d, J=8.3 Hz, 0.5H), 4.61 (t, J=4.6 Hz, 0.5H), 4.58 (d, J=4.7 Hz, 0.5H), 4.19-3.91 (m, 2.5H), 3.88 (d, J=4.6 Hz, 0.5H), 3.28-3.11 (m, 3H), 3.10-2.98 (m, 1H), 2.41-2.18 (m, 2.5H), 2.06 (s, 1.5H), 1.95-1.28 (m, 10H).

Example 98: (±)-(3,6′-dimethyl-[2,3′-bipyridin]-2′-yl)(2-(((5-fluoropyrimidin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Step A: (±)-tert-butyl 2-(((5-fluoropyrimidin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptane-7-carboxylate. To intermediate B-10 (500 mg, 2.2 mmol) in THF (11 mL) at 0° C. was added NaH (176 mg, 60 wt % in mineral oil, 4.4 mmol). After 15 min, 2-chloro-5-fluoropyrimidine (0.3 mL, 2.4 mmol) was added dropwise and the 0° C. ice bath was removed. After 12 h, H₂O was added and the reaction extracted with EtOAc. The combined organics dried (Na₂SO₄). Purification via silica gel chromatography (5-30% EtOAc in heptane) gave the title compound (490 mg, 69%) as a white solid. MS (ESI) mass calcd. for C₁₆H₂₂F₃N₃O₃, 323.4; m/z found 224.1 [M−100]⁺.

Step B: (±)-2-(((5-fluoropyrimidin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptane. To the title compound from step A (474 mg, 1.5 mmol) in 1,4-dioxane (1.5 mL) was added 6N HCl in iPrOH (1.5 mL). The reaction was heated to 40° C. for 1.5 h and concentrated to give the title compound that was used without further purification in subsequent steps. MS (ESI) mass calcd. for C₁₁H₁₄FN₃O, 223.1; m/z found 224.0 [M+H]⁺.

Step C: (±)-(3,6′-dimethyl-[2,3′-bipyridin]-2′-yl)(2-(((5-fluoropyrimidin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)methanone. Prepared analogous to example 2 substituting intermediate A-9 with 3,6′-dimethyl-[2,3′-bipyridine]-2′-carboxylic acid and intermediate B-10 with the title compound of Step B. MS (ESI) mass calcd. for C₂₄H₂₄FN₅O₂, 433.2; m/z found 434.2 [M+H]⁺. ¹H NMR (DMSO-D₆): 8.71 (s, 2H), 8.32 (t, J=4.5 Hz, 1H), 7.74 (d, J=7.9 Hz, 1H), 7.66 (t, J=7.3 Hz, 1H), 7.40 (d, J=7.9 Hz, 0.5H), 7.33-7.14 (m, 1.5H), 4.39 (br s, 0.5H), 4.34 (d, J=4.0 Hz, 0.5H), 4.27 (t, J=10.4 Hz, 0.5H), 4.10 (dd, J=5.2, 1.0 Hz, 0.5H), 3.90 (d, J=4.8 Hz, 0.5H), 3.85 (t, J=3.1 Hz, 0.5H), 3.69 (d, J=7.9 Hz, 1H), 2.55 (s, 1.5H), 2.31-2.20 (m, 0.5H), 2.18 (s, 1.5H), 2.16 (s, 1.5H), 2.12 (s, 1.5H), 2.01-1.82 (m, 0.5H), 1.81-1.14 (m, 6H).

Example 99: (±)-(2-(((5-fluoropyrimidin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)(6-methyl-3-(3-methylisoxazol-5-yl)pyridin-2-yl)methanone

Prepared analogous to example 98 substituting 3,6′-dimethyl-[2,3′-bipyridine]-2′-carboxylic acid with 6-methyl-3-(3-methylisoxazol-5-yl)picolinic acid. MS (ESI) mass calcd. for C₂₂H₂₂FN₅O₃, 423.2; m/z found 424.2 [M+H]⁺. ¹H NMR (DMSO-D₆): 8.71 (s, 1H), 8.66 (s, 1H), 8.12 (d, J=8.1 Hz, 0.4H), 8.09 (d, J=8.2 Hz, 0.6H), 7.50 (d, J=8.2 Hz, 0.4H), 7.40 (d, J=8.2 Hz, 0.6H), 6.64-6.63 (m, 1H), 4.68 (t, J=4.6 Hz, 0.6H), 4.60 (d, J=4.7 Hz, 0.4H), 4.11-3.90 (m, 2H), 3.62 (t, J=4.2 Hz, 0.4H), 3.55 (d, J=4.1 Hz, 0.5H), 2.55 (s, 1.2H), 2.40-2.15 (m, 4H), 2.16 (s, 1.8H), 1.88-1.12 (m, 6H).

Example 100: (±)-(2-(((5-fluoropyrimidin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)(6-methyl-3-(oxazol-2-yl)pyridin-2-yl)methanone

Prepared analogous to example 98 substituting 3,6′-dimethyl-[2,3′-bipyridine]-2′-carboxylic acid with intermediate A-43. MS (ESI) mass calcd. for C₂₁H₂₀FN₅O₃, 409.2; m/z found 410.2 [M+H]⁺. ¹H NMR (DMSO-D₆): 8.74 (s, 0.8H), 8.66 (s, 1.2H), 8.31-8.16 (m, 2H), 7.50 (d, J=8.2 Hz, 0.4H), 7.38 (t, J=8.9 Hz, 1.6H), 4.67 (t, J=4.5 Hz, 0.6H), 4.62 (d, J=4.7 Hz, 0.4H), 4.23 (t, J=10.1 Hz, 0.4H), 4.07 (dt, J=10.0, 6.2 Hz, 1.6H), 3.72 (t, J=4.2 Hz, 0.4H), 3.62 (d, J=4.4 Hz, 0.6H), 2.56 (s, 1.2H), 2.43-2.19 (m, 1H), 2.16 (s, 1.8H), 1.93-1.23 (m, 6H).

Example 101: (±)-(2-(((5-fluoropyrimidin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)(6-methyl-3-(pyrrolidin-1-yl)pyridin-2-yl)methanone

Prepared analogous to example 98 substituting 3,6′-dimethyl-[2,3′-bipyridine]-2′-carboxylic acid with 6-methyl-3-(pyrrolidin-1-yl)picolinic acid (example 68). MP=130° C.

Example 102: (±)-(2-(((5-fluoropyrimidin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)(6-methyl-3-(pyrimidin-2-yl)pyridin-2-yl)methanone

Prepared analogous to example 98 substituting 3,6′-dimethyl-[2,3′-bipyridine]-2′-carboxylic acid with intermediate A-9. MS (ESI) mass calcd. for C₂₂H₂₁FN₆O₂, 420.2; m/z found 421.2 [M+H]⁺. ¹H NMR (DMSO-D₆): 8.93 (d, J=4.9 Hz, 0.8H), 8.88 (d, J=4.9 Hz, 1.2H), 8.79 (s, 0.8H), 8.72 (s, 1.2H), 8.37-8.33 (m, 1H), 7.55-7.47 (m, 1.2H), 7.40 (d, J=8.1 Hz, 0.6H), 4.67-4.61 (br s, 0.6H), 4.59 (d, J=4.0 Hz, 0.4H), 4.33-4.22 (m, 1H), 4.18-4.07 (m, 1H), 3.91 (br s, 0.4H), 3.81 (d, J=3.4 Hz, 0.6H), 2.59 (s, 1.4H), 2.48-2.25 (m, 1H), 2.15 (s, 1.8H), 1.93-1.34 (m, 6H).

Example 103: (±)-(2-(((5-fluoropyrimidin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)(6-methyl-3-(4-methyl-1H-pyrazol-1-yl)pyridin-2-yl)methanone

Prepared analogous to example 98 substituting 3,6′-dimethyl-[2,3′-bipyridine]-2′-carboxylic acid with 6-methyl-3-(4-methyl-1H-pyrazol-1-yl)picolinic acid. MP=151.2° C. ¹H NMR (DMSO-D₆): 8.73 (s, 1H), 8.69 (s, 1H), 7.92 (d, J=5.0 Hz, 0.5H), 7.90 (d, J=5.0 Hz, 0.5H), 7.85 (d, J=2.3 Hz, 1H), 7.51-7.54 (m, 1.5H), 7.35 (d, J=8.4 Hz, 0.5H), 4.57 (t, J=4.5 Hz, 0.5H), 4.51 (d, J=4.7 Hz, 0.5H), 4.08-3.90 (m, 2H), 3.66 (t, J=4.0 Hz, 0.5H), 3.60 (d, J=4.0 Hz, 0.5H), 2.53 (s, 1.5H), 2.35-2.14 (m, 1H), 2.10 (s, 1.5H), 2.07 (s, 1.5H), 2.04 (s, 1.5H), 1.77-1.14 (m, 6H).

Example 104: (±)-(2-(((5-fluoropyrimidin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)(6-methyl-3-(1H-pyrazol-1-yl)pyridin-2-yl)methanone

Prepared analogous to example 98 substituting 3,6′-dimethyl-[2,3′-bipyridine]-2′-carboxylic acid with 6-methyl-3-(1H-pyrazol-1-yl)picolinic acid. MS (ESI) mass calcd. for C₂₁H₂₁FN₆O₂, 408.2; m/z found 409.2 [M+H]⁺. MP-119.2° C.

Example 105: (±)-(2-(((5-fluoropyridin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)(5-methyl-2 (2H-1,2,3-triazol-2-yl)phenyl)methanone

Prepared analogous to Example 7 substituting 6-methyl-3-(2H-1,2,3-triazol-2-yl)picolinic acid with 5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoic acid. (ESI) mass calcd. for C₂₂H₂₂FN₅O₂, 407.2; m/z found 408.2 [M+H]⁺. ¹H NMR (MeOD): 8.08-7.96 (m, 1H), 7.88 (s, 2H), 7.81-7.73 (m, 1H), 7.56-7.12 (m, 3H), 6.85-6.62 (m, 1H), 4.70-4.67 (m, 1H), 4.25-3.74 (m, 3H), 2.51-1.97 (m, 4H), 1.96-1.31 (m, 6H).

Example 106: (±)-(2,6-dimethoxyphenyl)(2-(((5-fluoropyridin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to example 105 substituting 5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoic acid with 2,6-dimethoxybenzoic acid. MS (ESI) mass calcd. for C₂₁H₂₃FN₂O₄, 386.2; m/z found 386.9 [M+H]⁺. ¹H NMR (MeOD): 8.02-7.93 (m, 1H), 7.57-7.40 (m, 1H), 7.39-7.21 (m, 1H), 6.87-6.63 (m, 2H), 6.62-6.38 (m, 1H), 4.83-4.65 (m, 1H), 4.49-4.07 (m, 1H), 4.07-3.52 (m, 8H), 2.48-2.09 (m, 1H), 2.06-1.07 (m, 6H).

Example 107: (±)-((3-fluoro-2-methoxyphenyl)(2-(((5-fluoropyridin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to example 105 substituting 5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoic acid with 3-fluoro-2-methoxybenzoic acid. MS (ESI) mass calcd. for C₂₀H₂₀F₂N₂O₃, 374.1; m/z found 375.1 [M+H]⁺. ¹H NMR (MeOD): 8.01-7.90 (m, 1H), 7.56-7.38 (m, 1H), 7.28-7.06 (m, 2H), 7.02-6.53 (m, 2H), 4.82-4.66 (m, 1H), 4.50-3.73 (m, 6H), 2.85-2.22 (m, 1H), 2.21-1.10 (m, 6H).

Example 108: (±)-(2-(((5-fluoropyridin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)(2-methoxy-6-(2H-1,2,3-triazol-2-yl)phenyl)methanone

Prepared analogous to example 105 substituting 5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoic acid with 2-methoxy-6-(2H-1,2,3-triazol-2-yl)benzoic acid. MS (ESI) mass calcd. for C₂₂H₂₂FN₅O₃, 423.2; m/z found 424.2 [M+H]⁺. ¹H NMR (MeOD): 8.10-7.74 (m, 3H), 7.66-7.41 (m, 3H), 7.25-6.88 (m, 1H), 6.88-6.43 (m, 1H), 4.78-4.64 (m, 1H), 4.51-3.57 (m, 6H), 2.48-0.94 (m, 7H).

Example 109: (±)-(5-fluoro-2-(1H-pyrazol-5-yl)phenyl)(2-(((5-fluoropyridin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to example 105 substituting 5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoic acid with 5-fluoro-2-(1H-pyrazol-5-yl)benzoic acid. MS (ESI) mass calcd. for C₂₂H₂₀F₂N₄O₂, 410.2; m/z found 411.2 [M+H]⁺. ¹H NMR (MeOD): 8.11-7.90 (m, 1H), 7.80-7.59 (m, 2H), 7.58-7.40 (m, 1H), 7.36-6.94 (m, 2H), 6.88-6.47 (m, 2H), 4.78-4.58 (m, 1H), 4.41-3.47 (m, 3H), 2.69-0.60 (m, 8H).

Example 110: (±)-(2-(((5-fluoropyridin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)(2-methyl-6-(2H-1,2,3-triazol-2-yl)phenyl)methanone

Prepared analogous to example 105 substituting 5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoic acid with 2-methyl-6-(2H-1,2,3-triazol-2-yl)benzoic acid. MS (ESI) mass calcd. for C₂₂H₂₂FN₅O₂, 407.2; m/z found 408.2 [M+H]⁺. ¹H NMR (MeOD): 8.11-7.62 (m, 4H), 7.59-6.48 (m, 4H), 4.78-4.68 (m, 1H), 4.50-3.37 (m, 3H), 2.80-0.82 (m, 10H).

Example 111: (±)-(2-(((5-fluoropyridin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)(6-methyl-3-(2H-1,2,3-triazol-2-yl)pyridin-2-yl)methanone

Prepared analogous to example 105 substituting 5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoic acid with 6-methyl-3-(2H-1,2,3-triazol-2-yl)picolinic acid. MS (ESI) mass calcd. for C₂₁H₂₁FN₆O₂, 408.2; m/z found 409.2 [M+H]⁺. ¹H NMR (MeOD): 8.28-8.19 (m, 1H), 8.06-7.88 (m, 3H), 7.57-7.35 (m, 2H), 6.89-6.60 (m, 1H), 4.76-4.73 (m, 1H), 4.32-4.02 (m, 2H), 3.93-3.80 (m, 1H), 2.70-2.20 (m, 4H), 2.05-1.42 (m, 6H).

Example 112: (±)-(5-chloro-3-(2H-1,2,3-triazol-2-yl)pyridin-2-yl)(2-(((5-fluoropyridin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to example 105 substituting 5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoic acid with sodium 5-chloro-3-(2H-1,2,3-triazol-2-yl)picolinate. MS (ESI) mass calcd. for C₂₀H₁₈ClFN₆O₂, 428.1; m/z found 429.1 [M+H]⁺. ¹H NMR (MeOD): 8.74-8.17 (m, 4H), 8.13-7.96 (m, 2H), 7.59-7.46 (m, 1H), 4.90-4.18 (m, 3H), 3.99 (s, 1H), 2.98-2.39 (m, 1H), 2.10-1.19 (m, 6H).

Example 113: (±)-(2-(((5-fluoropyridin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)(5-methoxy-3-(2H-1,2,3-triazol-2-yl)pyridin-2-yl)methanone

Prepared analogous to example 105 substituting 5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoic acid with sodium 5-methoxy-3-(2H-1,2,3-triazol-2-yl)picolinate. MS (ESI) mass calcd. for C₂₁H₂₁FN₆O₃, 424.2; m/z found 425.1 [M+H]⁺. ¹H NMR (MeOD): 8.37-7.79 (m, 5H), 7.56-7.40 (m, 1H), 6.87-6.59 (m, 1H), 4.73 (s, 1H), 4.30-3.82 (m, 6H), 2.48-2.11 (m, 1H), 2.07-1.42 (m, 6H).

Example 114: (±)-(2-(((5-fluoropyridin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)(5-methoxy-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone

Prepared analogous to example 105 substituting 5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoic acid with sodium 5-methoxy-2-(2H-1,2,3-triazol-2-yl)benzoate. MS (ESI) mass calcd. for C₂₂H₂₂FN₅O₃, 423.2; m/z found 424.2 [M+H]⁺. ¹H NMR (MeOD): 8.18-7.68 (m, 4H), 7.58-7.38 (m, 1H), 7.24-6.85 (m, 2H), 6.85-6.57 (m, 1H), 4.78-4.55 (m, 1H), 4.23-3.40 (m, 6H), 2.77-2.18 (m, 1H), 2.13-1.11 (m, 6H).

Example 115: (±)-(2-fluoro-6-(2H-1,2,3-triazol-2-yl)phenyl)(2-(((5-fluoropyridin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to example 105 substituting 5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoic acid with 2-fluoro-6-(2H-1,2,3-triazol-2-yl)benzoic acid. MS (ESI) mass calcd. for C₂₁H₁₉F₂N₅O₂, 411.2; m/z found 412.2 [M+H]⁺. ¹H NMR (MeOD): 8.11-7.71 (m, 4H), 7.69-7.24 (m, 3H), 6.98-6.43 (m, 1H), 4.83-4.67 (m, 1H), 4.53-3.34 (m, 3H), 2.50-0.96 (m, 7H).

Example 116: (±)-(4-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl)(2-(((5-fluoropyridin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to example 105 substituting 5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoic acid with 4-fluoro-2-(2H-1,2,3-triazol-2-yl)benzoic acid. MS (ESI) mass calcd. for C₂₁H₁₉F₂N₅O₂, 411.2; m/z found 412.2 [M+H]⁺. ¹H NMR (MeOD): 8.11-7.71 (m, 4H), 7.69-7.24 (m, 3H), 6.98-6.43 (m, 1H), 4.83-4.67 (m, 1H), 4.53-3.34 (m, 3H), 2.50-0.96 (m, 7H).

Example 117: (±)-(3-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl)(2-(((5-fluoropyridin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to example 105 substituting 5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoic acid with 3-fluoro-2-(2H-1,2,3-triazol-2-yl)benzoic acid. MS (ESI) mass calcd. for C₂₁H₁₉F₂N₅O₂, 411.2; m/z found 412.2 [M+H]⁺. ¹H NMR (MeOD): 8.14-7.85 (m, 3H), 7.70-7.18 (m, 4H), 6.81-6.65 (m, 1H), 4.67-4.32 (m, 1H), 4.24-3.79 (m, 3H), 2.42-2.24 (m, 1H), 1.97-1.32 (m, 6H).

Example 118: (±)-(3-ethoxy-6-methylpyridin-2-yl)(2-(((5-fluoropyridin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to example 105 substituting 5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoic acid with 3-ethoxy-6-methylpicolinic acid. MS (ESI) mass calcd. for C₂₁H₂₄FN₃O₃, 385.2; m/z found 385.9 [M+H]⁺. ¹H NMR (MeOD): 8.23-7.90 (m, 1H), 7.57-7.11 (m, 3H), 6.87-6.53 (m, 1H), 4.85-4.69 (m, 1H), 4.51-3.56 (m, 5H), 2.84-2.09 (m, 4H), 2.06-1.49 (m, 5H), 1.47-1.05 (m, 4H).

Example 119: (±)-(2-(((5-fluoropyridin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)(4-methoxy-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone

Prepared analogous to example 105 substituting 5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoic acid with 4-methoxy-2-(2H-1,2,3-triazol-2-yl)benzoic acid. MS (ESI) mass calcd. for C₂₂H₂₂FN₅O₃, 423.2; m/z found 424.2 [M+H]⁺. ¹H NMR (MeOD): 8.12-7.81 (m, 3H), 7.58-7.22 (m, 3H), 7.15-6.57 (m, 2H), 4.75-4.58 (m, 1H), 4.48-3.74 (m, 6H), 2.83-2.08 (m, 1H), 2.02-0.98 (m, 6H).

Example 120: (±)-(5-chloro-2-(2H-1,2,3-triazol-2-yl)phenyl)(2-(((5-fluoropyridin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to example 105 substituting 5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoic acid with 5-chloro-2-(2H-1,2,3-triazol-2-yl)benzoic acid. MS (ESI) mass calcd. for C₂₁H₁₉ClFN₅O₃, 427.2; m/z found 428.2 [M+H]⁺. ¹H NMR (MeOD): 8.13-7.77 (m, 4H), 7.70-7.31 (m, 3H), 6.87-6.60 (m, 1H), 4.80-4.60 (m, 1H), 4.51-3.67 (m, 3H), 2.84-2.22 (m, 1H), 2.07-1.11 (m, 6H).

Example 121: (±)-(2-(((5-fluoropyridin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)(4-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone

Prepared analogous to example 105 substituting 5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoic acid with 4-methyl-2-(2H-1,2,3-triazol-2-yl)benzoic acid. MS (ESI) mass calcd. for C₂₂H₂₂FN₅O₂, 407.2; m/z found 408.2 [M+H]⁺. ¹H NMR (MeOD): 8.10-7.84 (m, 3H), 7.76-7.69 (m, 1H), 7.56-6.87 (m, 3H), 6.87-6.53 (m, 1H), 4.75-4.59 (m, 1H), 4.49-3.65 (m, 3H), 2.80-2.09 (m, 4H), 2.01-1.00 (m, 6H).

Example 122: (±)-(2-(((5-fluoropyridin-2-yl)oxy)methyl)-7-azabicyclo 2.2.1 heptan-7-yl)(4-methyl-2-(pyrimidin-2-yl)phenyl)methanone

Prepared analogous to example 105 substituting 5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoic acid with 4-methyl-2-(pyrimidin-2-yl)benzoic acid. MS (ESI) mass calcd. for C₂₄H₂₃FN₄O₂, 418.2; m/z found 419.2 [M+H]⁺. ¹H NMR (MeOD): 8.94-8.89 (m, 1H), 8.84-8.81 (m, 1H), 8.08-7.94 (m, 2H), 7.60-7.46 (m, 1H), 7.45-7.33 (m, 2H), 7.22-6.99 (m, 1H), 6.90-6.58 (m, 1H), 4.78-4.62 (m, 1H), 4.52-3.78 (m, 3H), 2.73-2.19 (m, 4H), 2.07-1.05 (m, 6H).

Example 123: (±)-(2-(((5-fluoropyridin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)(2-methyl-6-(pyrimidin-2-yl)phenyl)methanone

Prepared analogous to example 105 substituting 5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoic acid with 2-methyl-6-(pyrimidin-2-yl)benzoic acid. MS (ESI) mass calcd. for C₂₄H₂₃FN₄O₂, 418.2; m/z found 419.2 [M+H]⁺. ¹H NMR (MeOD): 8.99-8.63 (m, 2H), 8.14-7.70 (m, 2H), 7.61-7.27 (m, 4H), 7.15-6.45 (m, 1H), 4.86-4.65 (m, 1H), 4.55-3.44 (m, 3H), 2.53-2.35 (m, 3H), 2.34-0.78 (m, 7H).

Example 124: (±)-(3-fluoro-2-(pyrimidin-2-yl)phenyl)(-2-(((5-fluoropyridin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to example 105 substituting 5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoic acid with 3-fluoro-2-(pyrimidin-2-yl)benzoic acid. MS (ESI) mass calcd. for C₂₃H₂₀F₂N₄O₂, 422.2; m/z found 422.8 [M+H]⁺. ¹H NMR (MeOD): 9.03-8.62 (m, 2H), 8.19-7.82 (m, 1H), 7.67-7.11 (m, 5H), 6.85-6.62 (m, 1H), 4.54 (s, 1H), 4.26-3.76 (m, 3H), 2.33 (s, 1H), 2.01-1.32 (m, 6H).

Example 125: (±)-(2-(((5-fluoropyridin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)(3-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone

Prepared analogous to example 105 substituting 5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoic acid with 3-methyl-2-(2H-1,2,3-triazol-2-yl)benzoic acid. MS (ESI) mass calcd. for C₂₂H₂₂FN₅O₂, 407.2; m/z found 408.2 [M+H]⁺. ¹H NMR (MeOD): 8.05-7.95 (m, 1H), 7.93-7.84 (m, 2H), 7.57-7.05 (m, 4H), 6.81-6.65 (m, 1H), 4.61-3.98 (m, 2H), 3.97-3.75 (m, 2H), 2.38-2.23 (m, 1H), 2.19-2.14 (m, 3H), 1.97-1.32 (m, 6H).

Example 126: (±)-(2-(((5-fluoropyridin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)(5-(hydroxymethyl)-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone

Step A: (±)-(5-bromo-2-(2H-1,2,3-triazol-2-yl)phenyl)(-2-(((5-fluoropyridin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)methanone. Prepared analogous to example 105 substituting 5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoic acid with 5-bromo-2-(2H-1,2,3-triazol-2-yl)benzoic acid.

Step B: (±)-methyl 3-(-2-(((5-fluoropyridin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptane-7-carbonyl)-4-(2H-1,2,3-triazol-2-yl)benzoate. The title compound of step A (100 mg, 0.2 mmol) and Pd(dppf)Cl₂ (35 mg) in MeOH (10 mL) was heated to 120° C. for 24 h in a sealed tube. The reaction was allowed to cool to rt and filtered. The filtrate was concentrated and purified via preparative TLC to give the title compound (20 mg, 21%).

Step C: (±)-(2-(((5-fluoropyridin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)(5-(hydroxymethyl)-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone. To the title compound of step B (40 mg, 0.1 mmol)) in MeOH (0.2 mL) and THF (6 mL) at 0° C. was added NaBH₄ (4 mg, 0.1 mmol). After stirring overnight at rt, the reaction was concentrated and purified directly via silica gel chromatography (EtOAc in petroleum ethers) to give the title compound. MS (ESI) mass calcd. for C₂₁H₂₁FN₆O₂, 408.2; m/z found 409.2 [M+H]⁺. ¹H NMR (MeOD): 8.07-7.82 (m, 4H), 7.66-7.29 (m, 3H), 6.85-6.60 (m, 1H), 4.70 (d, J=8.7 Hz, 2H), 4.50-3.73 (m, 4H), 2.43-2.20 (m, 1H), 2.04-1.28 (m, 6H).

Example 127: (±)-(2-(3-methyl-1,2,4-oxadiazol-5-yl)phenyl)(2-((pyridin-2-yloxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 2 substituting intermediate A-9 with 2-(3-methyl-1,2,4-oxadiazol-5-yl)benzoic acid. MS (ESI) mass calcd. for C₂₂H₂₂N₄O₃, 390.2; m/z found 391.1 [M+H]⁺. ¹H NMR (MeOD): 8.12-8.00 (m, 2H), 7.75-7.58 (m, 2H), 7.55-7.49 (m, 1H), 7.38-7.28 (m, 1H), 6.95-6.91 (m, 1H), 6.85-6.55 (m, 1H), 4.81-4.78 (m, 1H), 4.27-4.14 (m, 1H), 4.01-3.97 (m, 1H), 3.77-3.75 (m, 1H), 2.44-2.26 (m, 4H), 2.10-1.95 (m, 1H), 1.87-1.62 (m, 3H), 1.56-1.46 (m, 2H).

Example 128: (±)-(6-methyl-2-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)(2-((pyridin-2-yloxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 127 substituting 2-(3-methyl-1,2,4-oxadiazol-5-yl)benzoic acid with 6-methyl-2-(2H-1,2,3-triazol-2-yl)nicotinic acid. MS (ESI) mass calcd. for C₂₁H₂₂N₆O₂, 390.2; m/z found 391.2 [M+H]⁺. ¹H NMR (MeOD): 8.15-8.09 (m, 1H), 7.99 (s, 2H), 7.91-7.71 (m, 1H), 7.69-6.92 (m, 3H), 6.83-6.59 (m, 1H), 4.71-4.68 (m, 1H), 4.22-4.09 (m, 1H), 4.01-3.76 (m, 2H), 2.64-2.52 (m, 3H), 2.43-2.23 (m, 1H), 2.00-1.36 (m, 6H).

Example 129: (±)-(3-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl)(2-((pyridin-2-yloxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 127 substituting 2-(3-methyl-1,2,4-oxadiazol-5-yl)benzoic acid with 3-fluoro-2-(2H-1,2,3-triazol-2-yl)benzoic acid. MS (ESI) mass calcd. for C₂₁H₂₀FN₅O₂, 393.2; m/z found 394.0 [M+H]⁺. ¹H NMR (MeOD): 8.14-8.12 (m, 1H), 7.95-7.93 (m, 2H), 7.69-7.46 (m, 2H), 7.40-7.31 (m, 1H), 7.22-7.12 (m, 1H), 6.99-6.91 (m, 1H), 6.80-6.66 (m, 1H), 4.57-4.56 (m, 1H), 4.04-3.88 (m, 3H), 2.38-2.27 (m, 1H), 1.85-1.43 (m, 6H).

Example 130: (±)-(6-methyl-2-(1H-1,2,3-triazol-1-yl)pyridin-3-yl)(2-((pyridin-2-yloxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 127 substituting 2-(3-methyl-1,2,4-oxadiazol-5-yl)benzoic acid with 6-methyl-2-(1H-1,2,3-triazol-1-yl)nicotinic acid. MS (ESI) mass calcd. for C₂₁H₂₂N₆O₂, 390.2; m/z found 391.2 [M+H]⁺. ¹H NMR (MeOD): 8.62-8.61 (m, 1H), 8.12-8.09 (m, 1H), 7.99-7.73 (m, 2H), 7.71-7.62 (m, 1H), 7.50-6.91 (m, 2H), 6.87-6.61 (m, 1H), 4.74-4.71 (m, 1H), 4.17-3.79 (m, 3H), 2.64-2.53 (m, 3H), 2.46-2.26 (m, 1H), 2.06-1.90 (m, 1H), 1.83-1.38 (m, 5H).

Example 131: (±)-(6-methyl-2-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)(2-(((4-(trifluoromethyl)pyrimidin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Step A: (±)-tert-butyl 2-(((4-(trifluoromethyl)pyrimidin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptane-7-carboxylate. To intermediate B-10 (500 mg, 2.2 mmol) in THF (5 mL) at 0° C. was added NaH (6.6 mmol). After 30 min at rt, 2-chloro-4-(trifluoromethyl)pyrimidine (1.8 g, 9.9 mmol). The flask was then heated to 50° C. in an oil bath. After 3 h, H₂O was added and the reaction extracted with EtOAc (2×). Purification via silica gel chromatography (20% EtOAc in petroleum ethers) gave the title compound (752 mg, 92%).

Step B: (±)-2-(((4-(trifluoromethyl)pyrimidin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptane hydrochloride. To the title compound of step A (752 mg, 2 mmol) in MeOH (6 mL) was added HCl.

Step C: (±)-tert-butyl 2-(((4-(trifluoromethyl)pyrimidin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptane-7-carboxylate. Prepared analogous to example 127 substituting 2-(3-methyl-1,2,4-oxadiazol-5-yl)benzoic acid with 6-methyl-2-(2H-1,2,3-triazol-2-yl)nicotinic acid with the title compound of step B. MS (ESI) mass calcd. for C₂₁H₂₀F₃N₇O₂, 459.2; m/z found 460.2 [M+H]⁺. ¹H NMR (MeOD): 8.89-8.82 (m, 1H), 8.02-7.82 (m, 3H), 7.48-7.14 (m, 2H), 4.75-4.71 (m, 1H), 4.44-4.07 (m, 2H), 3.91-3.84 (m, 1H), 2.64-2.56 (m, 3H), 2.48-2.30 (m, 1H), 2.02-1.43 (m, 6H).

Example 132: (±)-(6-methyl-2-(1H-1,2,3-triazol-1-yl)pyridin-3-yl)(2-(((4-(trifluoromethyl)pyrimidin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 131 substituting 6-methyl-2-(2H-1,2,3-triazol-2-yl)nicotinic acid with 6-methyl-2-(1H-1,2,3-triazol-1-yl)nicotinic acid. MS (ESI) mass calcd. for C₂₁H₂₀F₃N₇O₂, 459.2; m/z found 460.2 [M+H]⁺. ¹H NMR (MeOD): 8.86-8.83 (m, 1H), 8.63-8.61 (m, 1H), 8.03-7.84 (m, 2H), 7.49-7.15 (m, 2H), 4.76-4.72 (m, 1H), 4.41-4.31 (m, 1H), 4.27-4.04 (m, 1H), 3.90-3.84 (m, 1H), 2.63-2.54 (m, 3H), 2.47-2.30 (m, 1H), 2.03-1.43 (m, 6H).

Example 133: (±)-(2-(3-methyl-1,2,4-oxadiazol-5-yl)phenyl)(2-(((4-(trifluoromethyl)pyrimidin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 131 substituting 6-methyl-2-(2H-1,2,3-triazol-2-yl)nicotinic acid with 2-(3-methyl-1,2,4-oxadiazol-5-yl)benzoic acid. MS (ESI) mass calcd. for C₂₂H₂₀F₃N₅O₂, 459.2; m/z found 460.2 [M+H]⁺. ¹H NMR (MeOD): 8.88-8.80 (m, 1H), 8.08-8.00 (m, 1H), 7.74-7.62 (m, 1H), 7.63-7.51 (m, 1H), 7.48-7.37 (m, 2H), 4.83-4.80 (m, 1H), 4.49-4.33 (m, 1H), 4.23-4.11 (m, 1H), 3.81-3.77 (m, 1H), 2.53-2.36 (m, 4H), 2.07-2.98 (m, 1H), 1.90-1.51 (m, 5H).

Example 134: (±)-(3-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl)(2-(((4-(trifluoromethyl)pyrimidin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 131 substituting 6-methyl-2-(2H-1,2,3-triazol-2-yl)nicotinic acid with 3-fluoro-2-(2H-1,2,3-triazol-2-yl)benzoic acid. MS (ESI) mass calcd. for C₂₁H₁₈F₄N₆O₂, 462.2; m/z found 463.2 [M+H]⁺. ¹H NMR (MeOD): 8.89-8.84 (m, 1H), 7.96-7.94 (m, 2H), 7.69-7.28 (m, 4H), 4.61-4.58 (m, 1H), 4.29-4.06 (m, 2H), 3.97-3.93 (m, 1H), 2.46-2.37 (m, 1H), 1.88-1.40 (m, 6H).

Example 135: (±)-(6-methyl-2-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)(2-(((5-methylpyridin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 131 substituting 2-chloro-4-(trifluoromethyl)pyrimidine with 2-chloro-5-methylpyridine. MS (ESI) mass calcd. for C₂₂H₂₄N₆O₂, 404.2; m/z found 405.2 [M+H]⁺. ¹H NMR (MeOD): 7.99-7.71 (m, 4H), 7.51-7.00 (m, 2H), 6.73-6.50 (m, 1H), 4.69 (d, J=3.6 Hz, 1H), 4.17-4.04 (m, 1H), 3.96-3.72 (m, 2H), 2.64-2.53 (m, 3H), 2.43-2.20 (m, 4H), 2.03-1.35 (m, 6H).

Example 136: (±)-(6-methyl-2-(1H-1,2,3-triazol-1-yl)pyridin-3-yl)(2-(((5-methylpyridin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 135 substituting 6-methyl-2-(2H-1,2,3-triazol-2-yl)nicotinic acid with 6-methyl-2-(1H-1,2,3-triazol-1-yl)nicotinic acid. MS (ESI) mass calcd. for C₂₂H₂₄N₆O₂, 404.2; m/z found 405.2 [M+H]⁺. ¹H NMR (MeOD): 8.62-8.55 (m, 1H), 8.19-7.88 (m, 3H), 7.75-7.47 (m, 2H), 7.05-6.52 (m, 1H), 4.72-4.71 (m, 1H), 4.08-4.02 (m, 1H), 3.98-3.74 (m, 2H), 2.64-2.53 (m, 3H), 2.37-2.24 (m, 4H), 1.96 (brs, 1H), 1.82-1.35 (m, 5H).

Example 137: (±)-(2-(3-methyl-1,2,4-oxadiazol-5-yl)phenyl)(2-(((5-methylpyridin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 135 substituting 6-methyl-2-(2H-1,2,3-triazol-2-yl)nicotinic acid with 2-(3-methyl-1,2,4-oxadiazol-5-yl)benzoic acid. MS (ESI) mass calcd. for C₂₃H₂₄N₄O₃, 404.2; m/z found 405.2 [M+H]⁺. ¹H NMR (MeOD): 8.09-8.00 (m, 1H), 7.92-7.88 (m, 1H), 7.75-7.63 (m, 1H), 7.55-7.43 (m, 2H), 7.38-7.29 (m, 1H), 6.76-6.47 (m, 1H), 4.81-4.77 (m, 1H), 4.22-4.09 (m, 1H), 3.95 (d, J=8.1 Hz, 1H), 3.76-3.74 (m, 1H), 2.44-2.20 (m, 7H), 2.07-1.97 (m, 1H), 1.86-1.62 (m, 3H), 1.55-1.42 (m, 2H).

Example 138: (±)-(3-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl)(2-(((5-methylpyridin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 135 substituting 6-methyl-2-(2H-1,2,3-triazol-2-yl)nicotinic acid with 3-fluoro-2-(2H-1,2,3-triazol-2-yl)benzoic acid. MS (ESI) mass calcd. for C₂₂H₂₂FN₅O₂, 407.2; m/z found 408.2 [M+H]⁺. ¹H NMR (MeOD): 7.96-7.93 (m, 3H), 7.69-7.49 (m, 2H), 7.40-7.33 (m, 1H), 7.22-7.13 (m, 1H), 6.71-6.58 (m, 1H), 4.58-4.55 (m, 1H), 4.02-3.83 (m, 3H), 2.37-2.23 (m, 4H), 1.85-1.41 (m, 6H).

Example 139: (±)-(6-methyl-2-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)(2-(((6-methylpyridin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 135 substituting 2-chloro-4-(trifluoromethyl)pyrimidine with 2-chloro-6-methylpyridine. MS (ESI) mass calcd. for C₂₂H₂₄N₆O₂, 404.2; m/z found 405.2 [M+H]⁺. ¹H NMR (MeOD): 7.99 (s, 2H), 7.91-7.69 (m, 1H), 7.56-6.77 (m, 3H), 6.60-6.38 (m, 1H), 4.70-4.69 (m, 1H), 4.21-4.05 (m, 1H), 3.98-3.77 (m, 2H), 2.64-2.51 (m, 3H), 2.43-2.20 (m, 4H), 2.03-1.37 (m, 6H).

Example 140: (±)-(6-methyl-2-(1H-1,2,3-triazol-1-yl)pyridin-3-yl)(2-(((6-methylpyridin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 139 substituting 6-methyl-2-(2H-1,2,3-triazol-2-yl)nicotinic acid with 6-methyl-2-(1H-1,2,3-triazol-1-yl)nicotinic acid. MS (ESI) mass calcd. for C₂₂H₂₄N₆O₂, 404.2; m/z found 405.2 [M+H]⁺. ¹H NMR (MeOD): 8.34 (d, J=7.1 Hz, 1H), 7.77-7.42 (m, 3H), 7.28-6.35 (m, 3H), 4.82-4.79 (m, 1H), 4.24-3.94 (m, 2H), 3.87-3.81 (m, 1H), 2.63-2.22 (m, 7H), 2.15-1.98 (m, 1H), 1.84-1.34 (m, 5H).

Example 141: (±)-(2-(3-methyl-1,2,4-oxadiazol-5-yl)phenyl)(2-(((6-methylpyridin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 139 substituting 6-methyl-2-(2H-1,2,3-triazol-2-yl)nicotinic acid with 2-(3-methyl-1,2,4-oxadiazol-5-yl)benzoic acid. MS (ESI) mass calcd. for C₂₃H₂₄N₄O₃, 404.2; m/z found 405.2 [M+H]⁺. ¹H NMR (MeOD): 8.10-8.00 (m, 1H), 7.75-7.63 (m, 1H), 7.57-7.47 (m, 2H), 7.37-7.26 (m, 1H), 6.79 (dd, J=7.2, 2.8 Hz, 1H), 6.64-6.35 (m, 1H), 4.81-4.78 (m, 1H), 4.25-4.11 (m, 1H), 3.98-3.95 (m, 1H), 3.79-3.74 (m, 1H), 2.42-2.25 (m, 7H), 2.08-1.95 (m, 1H), 1.86-1.63 (m, 3H), 1.58-1.44 (m, 2H).

Example 142: (±)-(3-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl)(2-(((6-methylpyridin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 139 substituting 6-methyl-2-(2H-1,2,3-triazol-2-yl)nicotinic acid with 3-fluoro-2-(2H-1,2,3-triazol-2-yl)benzoic acid. MS (ESI) mass calcd. for C₂₂H₂₂FN₅O₂, 407.2; m/z found 408.2 [M+H]⁺. ¹H NMR (MeOD): 7.95-7.93 (m, 2H), 7.68-7.47 (m, 2H), 7.40-7.31 (m, 1H), 7.21-7.09 (m, 1H), 6.80 (t, J=8.3 Hz, 1H), 6.58-6.46 (m, 1H), 4.56 (s, 1H), 4.01 (d, J=7.3 Hz, 1H), 3.91 (d, J=7.4 Hz, 2H), 2.43 (d, J=2.5 Hz, 3H), 2.38-2.28 (m, 1H), 1.83-1.45 (m, 6H).

Example 143: (±)-(6-methyl-2-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)(2-(((6-(trifluoromethyl)pyridin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 131 substituting 2-chloro-4-(trifluoromethyl)pyrimidine with 2-chloro-6-(trifluoromethyl)pyridine. MS (ESI) mass calcd. for C₂₂H₂₁F₃N₆O₂, 458.2; m/z found 459.2 [M+H]⁺. ¹H NMR (MeOD): 7.91 (s, 1H), 7.84 (s, 1H), 7.73-7.65 (m, 2H), 7.29-7.25 (m, 2H), 6.93-6.69 (m, 1H), 4.85-4.82 (m, 1H), 4.25-4.16 (m, 1H), 3.98-3.96 (m, 1H), 3.79-3.69 (m, 1H), 2.69-2.56 (m, 3H), 2.38-2.16 (m, 1H), 2.05-1.24 (m, 6H).

Example 144: (±)-(6-methyl-2-(1H-1,2,3-triazol-1-yl)pyridin-3-yl)(2-(((6-(trifluoromethyl)pyridin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 143 substituting 6-methyl-2-(2H-1,2,3-triazol-2-yl)nicotinic acid with 6-methyl-2-(1H-1,2,3-triazol-1-yl)nicotinic acid. MS (ESI) mass calcd. for C₂₂H₂₁F₃N₆O₂, 458.2; m/z found 459.2 [M+H]⁺. ¹H NMR (MeOD): 8.61 (t, J=1.1 Hz, 1H), 8.00-7.72 (m, 3H), 7.49-6.83 (m, 3H), 4.75-4.71 (m, 1H), 4.31-4.10 (m, 1H), 4.08-3.95 (m, 1H), 3.89-3.77 (m, 1H), 2.64-2.52 (m, 3H), 2.43-2.27 (m, 1H), 2.06-1.89 (m, 1H), 1.82-1.37 (m, 5H).

Example 145: (±)-(2-(3-methyl-1,2,4-oxadiazol-5-yl)phenyl)(2-(((6-(trifluoromethyl)pyridin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 143 substituting 6-methyl-2-(2H-1,2,3-triazol-2-yl)nicotinic acid with 2-(3-methyl-1,2,4-oxadiazol-5-yl)benzoic acid. MS (ESI) mass calcd. for C₂₃H₂₁FN₄O₃, 458.2; m/z found 459.2 [M+H]⁺. ¹H NMR (MeOD): 8.10-8.01 (m, 1H), 7.88-7.77 (m, 1H), 7.75-7.63 (m, 1H), 7.54-7.49 (m, 1H), 7.39-7.25 (m, 2H), 7.07-6.78 (m, 1H), 4.82-4.79 (m, 1H), 4.35-4.24 (m, 1H), 4.10-4.07 (m, 1H), 3.78-3.74 (m, 1H), 2.48-2.29 (m, 4H), 2.09-1.96 (m, 1H), 1.88-1.63 (m, 3H), 1.58-1.47 (m, 2H).

Example 146: (±)-(3-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl)(2-(((6-(trifluoromethyl)pyridin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 143 substituting 6-methyl-2-(2H-1,2,3-triazol-2-yl)nicotinic acid with 3-fluoro-2-(2H-1,2,3-triazol-2-yl)benzoic acid. MS (ESI) mass calcd. for C₂₂H₁₉F₄N₅O₂, 461.2; m/z found 462.0 [M+H]⁺. ¹H NMR (MeOD): 7.95-7.93 (m, 2H), 7.86-7.80 (m, 1H), 7.68-7.12 (m, 4H), 7.02-6.86 (m, 1H), 4.59-4.56 (m, 1H), 4.10-3.86 (m, 3H), 2.38-2.30 (m, 1H), 1.95-1.45 (m, 6H).

Example 147: (±)-(6-methyl-2-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)(2-((quinoxalin-2-yloxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 131 substituting 2-chloro-4-(trifluoromethyl)pyrimidine with 2-chloroquinoxaline. MS (ESI) mass calcd. for C₂₄H₂₃N₇O₂, 441.2; m/z found 442.2 [M+H]⁺. ¹H NMR (MeOD): 8.47-8.04 (m, 2H), 7.98-7.69 (m, 5H), 7.65-7.56 (m, 1H), 7.45-6.73 (m, 1H), 4.77-4.71 (m, 1H), 4.46-4.10 (m, 2H), 3.91-3.79 (m, 1H), 2.64-2.32 (m, 4H), 2.03-1.38 (m, 6H).

Example 148: (±)-(6-methyl-2-(1H-1,2,3-triazol-1-yl)pyridin-3-yl)(2-((quinoxalin-2-yloxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 147 substituting 6-methyl-2-(2H-1,2,3-triazol-2-yl)nicotinic acid with 6-methyl-2-(1H-1,2,3-triazol-1-yl)nicotinic acid. MS (ESI) mass calcd. for C₂₄H₂₃N₇O₂, 441.2; m/z found 441.2 [M+H]⁺. ¹H NMR (MeOD): 8.61-8.59 (m, 1H), 8.46-8.25 (m, 1H), 8.04-7.55 (m, 6H), 7.48-6.74 (m, 1H), 4.78-4.74 (m, 1H), 4.43-4.30 (m, 1H), 4.21-4.18 (m, 1H), 3.92-3.82 (m, 1H), 2.63-2.34 (m, 4H), 2.08-1.89 (m, 1H), 1.88-1.39 (m, 5H).

Example 149: (±)-(2-(3-methyl-1,2,4-oxadiazol-5-yl)phenyl)(2-((quinoxalin-2-yloxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 147 substituting 6-methyl-2-(2H-1,2,3-triazol-2-yl)nicotinic acid with 2-(3-methyl-1,2,4-oxadiazol-5-yl)benzoic acid. MS (ESI) mass calcd. for C₂₅H₂₃N₅O₃, 441.2; m/z found 442.2 [M+H]⁺. ¹H NMR (MeOD): 8.48-8.20 (m, 1H), 8.08-7.91 (m, 2H), 7.83-7.12 (m, 6H), 4.86-4.81 (m, 1H), 4.50-4.36 (m, 1H), 4.26-4.18 (m, 1H), 3.80-3.77 (m, 1H), 2.55-2.34 (m, 4H), 2.09-1.97 (m, 1H), 1.91-1.64 (m, 3H), 1.61-1.50 (m, 2H).

Example 150: (±)-(3-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl)(2-((quinoxalin-2-yloxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 147 substituting 6-methyl-2-(2H-1,2,3-triazol-2-yl)nicotinic acid with 3-fluoro-2-(2H-1,2,3-triazol-2-yl)benzoic acid. MS (ESI) mass calcd. for C₂₄H₂₁FN₆O₂, 444.2; m/z found 445.1 [M+H]⁺. ¹H NMR (MeOD): 8.47-8.33 (m, 1H), 8.01-7.60 (m, 6H), 7.54-6.92 (m, 3H), 4.65-4.60 (m, 1H), 4.31-4.13 (m, 2H), 3.96-3.95 (m, 1H), 2.52-2.40 (m, 1H), 1.96-1.44 (m, 6H).

Example 151: (±)-(2-(((4,6-dimethylpyrimidin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)(6-methyl-2-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)methanone

Prepared analogous to Example 131 substituting 2-chloro-4-(trifluoromethyl)pyrimidine with 2-chloro-4,6-dimethylpyrimidine. MS (ESI) mass calcd. for C₂₂H₂₅N₇O₂, 419.2; m/z found 420.2 [M+H]⁺. ¹H NMR (MeOD): 8.02-7.99 (m, 2H), 7.94-7.46 (m, 1H), 7.48-7.10 (m, 1H), 6.87 (s, 1H), 4.72-4.71 (m, 1H), 4.38-3.97 (m, 2H), 3.89-3.84 (m, 1H), 2.65-2.17 (m, 10H), 1.98-1.37 (m, 6H).

Example 152: (±)-(2-(((4,6-dimethylpyrimidin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)(6-methyl-2-(1H-1,2,3-triazol-1-yl)pyridin-3-yl)methanone

Prepared analogous to Example 151 substituting 6-methyl-2-(2H-1,2,3-triazol-2-yl)nicotinic acid with 6-methyl-2-(1H-1,2,3-triazol-1-yl)nicotinic acid. MS (ESI) mass calcd. for C₂₂H₂₅N₇O₂, 419.2; m/z found 420.2 [M+H]⁺. ¹H NMR (MeOD): 8.62-8.61 (m, 1H), 7.98-7.78 (m, 2H), 7.50-7.11 (m, 1H), 6.86 (d, J=9.7 Hz, 1H), 4.75-4.71 (m, 1H), 4.25-4.23 (m, 1H), 4.16-3.84 (m, 2H), 2.64-2.55 (m, 3H), 2.46-2.25 (m, 7H), 2.06-1.88 (m, 1H), 1.85-1.39 (m, 5H).

Example 153: (±)-(2-(((4,6-dimethylpyrimidin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)(2-(3-methyl-1,2,4-oxadiazol-5-yl)phenyl)methanone

Prepared analogous to Example 151 substituting 6-methyl-2-(2H-1,2,3-triazol-2-yl)nicotinic acid with 2-(3-methyl-1,2,4-oxadiazol-5-yl)benzoic acid. MS (ESI) mass calcd. for C₂₃H₂₅N₅O₃, 419.2; m/z found 420.2 [M+H]⁺. ¹H NMR (MeOD): 8.10-8.01 (m, 1H), 7.76-7.64 (m, 1H), 7.58-7.51 (m, 1H), 7.42-7.36 (m, 1H), 6.86 (s, 1H), 4.83-4.80 (m, 1H), 4.42-4.22 (m, 1H), 4.13-4.00 (m, 1H), 3.83-3.76 (m, 1H), 2.49-2.28 (m, 10H), 2.08-1.98 (m, 1H), 1.89-1.65 (m, 3H), 1.58-1.48 (m, 2H).

Example 154: (±)-(2-(((4,6-dimethylpyrimidin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)(3-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone

Prepared analogous to Example 151 substituting 6-methyl-2-(2H-1,2,3-triazol-2-yl)nicotinic acid with 3-fluoro-2-(2H-1,2,3-triazol-2-yl)benzoic acid. MS (ESI) mass calcd. for C₂₂H₂₃FN₆O₂, 422.2; m/z found 423.1 [M+H]⁺. ¹H NMR (MeOD): 7.96-7.95 (m, 2H), 7.69-7.22 (m, 3H), 6.87 (d, J=5.8 Hz, 1H), 4.58-4.56 (m, 1H), 4.19-3.89 (m, 3H), 2.42-2.34 (m, 7H), 1.90-1.37 (m, 6H).

Example 155: (±)-(2-ethoxy-4-methylpyridin-3-yl)(2-((pyridin-2-yloxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 1 substituting intermediate B-9 with B-10 and 5-fluoro-2-(pyrimidin-2-yl)benzoic acid with 2-ethoxy-4-methylnicotinic acid. MS (ESI) mass calcd. for C₂₁H₂₅N₃O₃, 367.2; m/z found 368.3 [M+H]⁺. ¹H NMR (CDCl₃): 8.13-8.05 (m, 1H), 7.99-7.87 (m, 1H), 7.58-7.46 (m, 1H), 6.87-6.79 (m, 1H), 6.76-6.67 (m, 1H), 6.55-6.49 (m, 1H), 4.92-4.84 (m, 1H), 4.43-3.64 (m, 5H), 2.43-1.22 (m, 13H).

Example 156: (±)-(6-methylimidazo[2,1-b]thiazol-5-yl)(2-((pyridin-2-yloxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 1 substituting intermediate B-9 with B-10 and 5-fluoro-2-(pyrimidin-2-yl)benzoic acid with 6-methylimidazo[2,1-b]thiazole-5-carboxylic acid. ¹H NMR (CDCl₃): 8.05-7.98 (m, 1H), 7.79 (d, J=4.5 Hz, 1H), 7.54-7.47 (m, 1H), 6.84-6.78 (m, 1H), 6.76 (d, J=4.5 Hz, 1H), 6.62 (d, J=8.4 Hz, 1H), 4.54-4.35 (m, 2H), 4.11-4.03 (m, 1H), 4.02-3.88 (m, 1H), 2.46 (s, 3H), 2.39-2.28 (m, 1H), 2.07-1.97 (m, 1H), 1.80-1.70 (m, 2H), 1.65-1.52 (m, 3H).

Example 157: (±)-(5-bromo-2-ethoxypyridin-3-yl)(2-((pyridin-2-yloxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 1 substituting intermediate B-9 with B-10 and 5-fluoro-2-(pyrimidin-2-yl)benzoic acid with 5-bromo-2-ethoxynicotinic acid. MS (ESI) mass calcd. for C₂₀H₂₂BrN₃O₃, 431.1; m/z found 432.2 [M+H]⁺. ¹H NMR (CDCl₃): 8.33-8.07 (m, 2H), 7.74 (d, J=2.5 Hz, 0.5H), 7.61 (d, J=2.5 Hz, 0.5H), 7.59-7.49 (m, 1H), 6.89-6.81 (m, 1H), 6.75 (d, J=8.3 Hz, 0.5H), 6.55 (d, J=8.4 Hz, 0.5H), 4.86-4.80 (m, 1H), 4.48-3.78 (m, 5H), 2.43-2.33 (m, 0.5H), 2.32-2.23 (m, 0.5H), 2.03-1.39 (m, 6H), 1.37-1.29 (m, 3H).

Example 158: (±)-(2-ethoxy-6-methylpyridin-3-yl)(2-((pyridin-2-yloxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 1 substituting intermediate B-9 with intermediate B-10 and 5-fluoro-2-(pyrimidin-2-yl)benzoic acid with 2-ethoxy-6-methylnicotinic acid. MS (ESI) mass calcd. for C₂₁H₂₅N₃O₃, 367.2; m/z found 368.3 [M+H]⁺. ¹H NMR (CDCl₃): 8.14-8.08 (m, 1H), 7.57-7.47 (m, 1.5H), 7.38 (d, J=7.4 Hz, 0.5H), 6.86-6.82 (m, 1H), 6.74 (d, J=8.3 Hz, 0.5H), 6.72 (d, J=7.4 Hz, 0.5H), 6.51 (d, J=8.3 Hz, 0.5H), 6.46 (d, J=7.4 Hz, 0.5H), 4.84-4.79 (m, 1H), 4.44-4.34 (m, 1.5H), 4.27-4.09 (m, 1.5H), 4.06-4.01 (m, 0.5H), 3.92-3.80 (m, 1.5H), 2.43 (s, 1.5H), 2.38-2.32 (m, 2H), 2.26-2.20 (m, 0.5H), 2.01-1.40 (m, 6H), 1.36-1.28 (m, 3H).

Example 159: (±)-(7-hydroxyquinolin-8-yl)(2-((pyridin-2-yloxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 1 substituting intermediate B-9 with intermediate B-10 and 5-fluoro-2-(pyrimidin-2-yl)benzoic acid with 7-hydroxyquinoline-8-carboxylic acid (intermediate A-29 step B). MS (ESI) mass calcd. for C₂₂H₂₁N₃O₃, 375.2; m/z found 376.3 [M+H]⁺. ¹H NMR (CDCl₃): 8.88-8.66 (m, 1H), 8.19-7.93 (m, 2H), 7.80-7.41 (m, 2H), 7.26-6.25 (series of m, 4H), 5.10-4.87 (m, 1H), 4.34-3.60 (m, 3H), 2.51-1.00 (series of m, 7H).

Example 160: (±)-(2-ethoxy-5-phenylpyridin-3-yl)(2-((pyridin-2-yloxy)methyl)-7-azabicyclo[2.2.1]heptan-7-1)methanone

Prepared analogous to Example 1 substituting intermediate B-9 with intermediate B-10 and 5-fluoro-2-(pyrimidin-2-yl)benzoic acid with 2-ethoxy-5-phenylnicotinic acid. MS (ESI) mass calcd. for C₂₆H₂₇N₃O₃, 429.2; m/z found 430.2 [M+H]⁺. ¹H NMR (CDCl₃): 8.40 and 8.30 (2d, J=2.5 Hz, 1H), 8.15-8.12 and 7.98-7.94 (2m, 1H), 7.87 and 7.74 (2d, J=2.5 Hz, 1H), 7.59-7.28 (m, 6H), 6.88-6.83 and 6.72-6.68 (2m, 1H), 6.76 and 6.47 (2d, J=8.3 Hz, 1H), 4.89-4.84 (m, 1H), 4.34-3.84 (series of m, 5H), 2.43-2.34 and 2.32-2.23 (m, 1H), 2.06-1.45 (series of m, 6H), 1.42-1.32 (m, 3H).

Example 161: (±)-(4-bromo-2-ethoxypyridin-3-yl)(2-((pyridin-2-yloxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 1 substituting intermediate B-9 with intermediate B-10 and 5-fluoro-2-(pyrimidin-2-yl)benzoic acid with 4-bromo-2-ethoxynicotinic acid. MS (ESI) mass calcd. for C₂₀H₂₂BrN₃O₃, 431.1; m/z found 432.2 [M+H]⁺. ¹H NMR (CDCl₃): 8.15-8.08 (m, 1H), 7.96-7.87 (m, 1H), 7.60-7.49 (m, 1H), 7.11-6.92 (series of m, 1H), 6.88-6.82 (m, 1H), 6.78-6.52 (series of m, 1H), 4.94-4.87 (m, 1H), 4.47-3.67 (series of m, 5H), 2.45-1.41 (series of m, 7H), 1.38-1.27 (m, 3H).

Example 162: (±)-(2-chloro-4-ethoxypyridin-3-yl)(2-((pyridin-2-yloxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 1 substituting intermediate B-9 with intermediate B-10 and 5-fluoro-2-(pyrimidin-2-yl)benzoic acid with 2-chloro-4-ethoxynicotinic acid. MS (ESI) mass calcd. for C₂₀H₂₂ClN₃O₃, 387.1; m/z found 388.3 [M+H]⁺. ¹H NMR (CDCl₃): 8.27-8.17 (m, 1H), 8.15-8.07 (m, 1H), 7.60-7.48 (m, 1H), 6.88-6.82 (m, 1H), 6.80-6.73 (m, 1H), 6.58-6.49 (m, 1H), 4.93-4.87 (m, 1H), 4.27-4.02 (m, 3H), 3.92-3.58 (series of m, 2H), 2.44-1.35 (series of m, 10OH).

Example 163: (±)-(2,4-diethoxypyridin-3-yl)(2-((pyridin-2-yloxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 1 substituting intermediate B-9 with intermediate B-10 and 5-fluoro-2-(pyrimidin-2-yl)benzoic acid with 2,4-diethoxynicotinic acid. MS (ESI) mass calcd. for C₂₂H₂₇BrN₃O₄, 397.2; m/z found 398.2 [M+H]⁺. ¹H NMR (CDCl₃): 8.15-8.07 (m, 1H), 8.03-7.94 (m, 1H), 7.60-7.46 (m, 1H), 6.87-6.80 (m, 1H), 6.77-6.73 (m, 0.5H), 6.56-6.45 (m, 1H), 6.30-6.27 (m, 0.5H) 4.88-4.83 (m, 1H), 4.50-3.51 (series of m, 7H), 2.40-1.15 (series of m, 13H).

Example 164: (3-ethoxyisoquinolin-4-yl)((1S,2R,4R)-2-((pyridin-2-yloxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 1 substituting 5-fluoro-2-(pyrimidin-2-yl)benzoic acid with intermediate A-22. MS (ESI) mass calcd. for C₂₄H₂₅N₃O₃, 403.2; m/z found 404.2 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) 8.97-8.89 (m, 0.7H), 8.87-8.81 (m, 0.3H), 8.22-8.07 (m, 0.7H), 7.95-7.85 (m, 1H), 7.82 (dq, J=8.6, 0.9 Hz, 0.2H), 7.78-7.69 (m, 0.6H), 7.69-7.47 (m, 2H), 7.43-7.28 (m, 1.2H), 7.10 (ddd, J=8.0, 6.8, 1.0 Hz, 0.3H), 6.93-6.68 (m, 1.5H), 6.52-6.46 (m, 0.2H), 6.16-6.09 (m, 0.3H), 5.02 (td, J=9.5, 4.6 Hz, 1H), 4.65-3.99 (m, 3.5H), 3.92 (dd, J=10.5, 5.6 Hz, 0.25H), 3.74-3.58 (m, 1.25H), 2.52-2.29 (m, 0.5H), 2.27-1.93 (m, 2H), 1.86-0.78 (m, 7.5H).

Example 165: (±)-(2-ethoxyphenyl)(2-(((5-fluoropyridin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 7 substituting 6-methyl-3-(2H-1,2,3-triazol-2-yl)picolinic acid with 2-ethoxybenzoic acid. ¹H NMR (400 MHz, CDCl₃): 7.95 (dd, J=7.3, 3.1 Hz, 1H), 7.37-7.18 (m, 2.5H), 7.14 (dd, J=7.4, 1.7 Hz, 0.5H), 6.95 (td, J=7.5, 0.9 Hz, 0.5H), 6.90 (dd, J=8.4, 1.0 Hz, 0.5H), 6.83-6.68 (m, 1.5H), 6.47 (dd, J=9.0, 3.6 Hz, 0.5H), 4.88-4.80 (m, 1H), 4.17-3.72 (m, 5H), 2.40-2.28 (m, 0.5H), 2.26-2.14 (m, 0.5H), 2.07-1.85 (m, 2H), 1.83-1.17 (m, 7H).

Example 166: (±)-(5-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl)(2-((quinoxalin-2-yloxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 2 substituting 6-methyl-3-(2H-1,2,3-triazol-2-yl)picolinic acid with intermediate A-10 and 2-fluoropyridine with 2-chloroquinoxaline. MS (ESI) mass calcd. for C₂₄H₂₁FN₆O₂, 444.2; m/z found 445.2 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃): 8.49 (s, 0.4H), 8.30 (s, 0.4H), 8.04 (ddd, J=8.2, 6.9, 1.5 Hz, 1H), 7.90-7.76 (m, 2.5H), 7.75-7.66 (m, 1.5H), 7.65-7.55 (m, 1.5H), 7.44 (dd, J=8.5, 5.8 Hz, 0.5H), 7.32 (dd, J=8.5, 5.8 Hz, 0.5H), 7.29-7.22 (m, 0.2H), 7.21-7.10 (m, 1H), 6.49 (s, 0.5H), 4.93-4.84 (m, 1H), 4.52-4.30 (m, 1H), 4.23-4.07 (m, 1H), 3.87-3.78 (m, 1H), 2.48-2.25 (m, 1.8H), 2.10-1.88 (m, 1.2H), 1.83-1.31 (m, 4H).

Example 167: (±)-5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl)(2-(((5-methylpyridin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 13 substituting 2-chloro-4-trfluoromethylpyrimidine with 2-fluoro-5-methylpyridine. MS (ESI) mass calcd. for C₂₃H₂₅N₅O₂, 403.2; m/z found 404.2 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃): 7.99-7.92 (m, 1H), 7.81-7.68 (m, 2.5H), 7.42-7.29 (m, 1.5H), 7.26-7.21 (m, 0.5H), 7.21-7.10 (m, 1H), 6.66 (d, J=8.4 Hz, 0.5H), 6.45 (d, J=8.4 Hz, 0.5H), 4.85-4.73 (m, 1H), 4.16-3.68 (m, 3H), 2.42 (s, 1.3H), 2.34-2.14 (m, 3.7H), 2.02-1.79 (m, 2.5H), 1.72-1.21 (m, 5.5H).

Example 168: (±)-(6-methyl-2-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)(2-((quinoxalin-2-yloxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 1 substituting intermediate B-9 with intermediate B-10, 2-fluoropyridine with 2-chloroquinoxaline and 5-fluoro-2-(pyrimidin-2-yl)benzoic acid with intermediate A-3 to give the title compound. MS (ESI) mass calcd. for C₂₄H₂₃N₇O₂, 441.2; m/z found 442.2 [M+H]⁺. ¹H NMR CD₃OD: 8.47-8.04 (m, 2H), 7.98-7.69 (m, 5H), 7.65-7.56 (m, 1H), 7.45-6.73 (m, 1H), 4.77-4.71 (m, 1H), 4.46-4.10 (m, 2H), 3.91-3.79 (m, 1H), 2.64-2.32 (m, 4H), 2.03-1.38 (m, 6H).

Example 169: (±)-(5-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl)(2-((pyridin-2-ylamino)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to example 170 substituting 2-chloro-4,6-dimethylpyrimidine with 2-fluoropyridine. MS (ESI) mass calcd. for C₂₁H₂₁FN₆O, 392.2; m/z found 393.1 [M+H]⁺. 1H NMR (CD3OD): 8.02-7.83 (m, 4H), 7.47-7.23 (m, 3H), 6.59-6.38 (m, 2H), 4.73-4.55 (m, 1H), 3.87-3.70 (m, 1H), 3.24-2.80 (m, 2H), 2.27-2.03 (m, 1H), 1.97-1.34 (m, 6H).

Example 170: (±)-(2-(((4,6-dimethylpyrimidin-2-yl)amino)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)(5-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone

Step A: (±)-tert-butyl 2-(((methylsulfonyl)oxy)methyl)-7-azabicyclo[2.2.1]heptane-7-carboxylate. To intermediate B-10 (2.6 g, 11.5 mmol) and TEA (1.7 g, 17.2 mmol) in DCM (15 mL) at 0° C. was added MsCl (1.6 g, 13.7 mmol) dropwise over 10m. This ice bath was removed and the reaction was allowed to proceed at rt for 12 h and H2O was added. The layers were separated and the organic layer was washed with brine and dried (Na2SO4). Purification via silica gel chromatography (15% EtOAc in petroleum ethers) gave the title compound (3.5 g).

Step B: (±)-tert-butyl 2-(azidomethyl)-7-azabicyclo[2.2.1]heptane-7-carboxylate. To the title compound of step A (3.4 g, 11.1 mmol) in DMF (15 mL) was added sodium azide (2.1 g, 33.4 mmol). The mixture was heated at 100° C. overnight, cooled to rt, poured into H₂O and extracted with DCM. The combined organics were washed with brine and dried (Na₂SO₄). Purification via silica gel chromatography (10% EtOAc in petroleum ethers) gave the title compound (2.6 g).

Step C: (±)-2-(azidomethyl)-7-azabicyclo[2.2.1]heptane. To the title compound of step B in DCM was added TFA. After 3 h at rt, the reaction mixture was concentrated to give the title compound (1.7 g) as the TFA salt.

Step D: (±)-2-(azidomethyl)-7-azabicyclo[2.2.1]heptan-7-yl)(5-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone. Prepared analogous to example 22 substituting 2-(2H-1,2,3-triazol-2-yl)benzoic acid with 5-fluoro-2-(2H-1,2,3-triazol-2-yl)benzoic acid and using the title compound of step C.

Step E: 2-(aminomethyl)-7-azabicyclo[2.2.1]heptan-7-yl)(5-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone. The title compound of step D in MeOH was hydrogenated under an atmosphere of hydrogen in the presence of 10 wt % Pd/C for 4 h. The catalyst was removed by filtration. Purification via silica gel chromatography (7% MeOH in DCM) gave the title compound.

Step F: (±)-(2-(((4,6-dimethylpyrimidin-2-yl)amino)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)(5-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone. To the title compound of step E (30 mg) in NMP (3 mL) was added 2-chloro-4,6-dimethylpyrimidine (16 mg) and Cs₂CO₃ (43 mg). The reaction was heated to 180° C. for 2 h. After cooling to rt, H₂O was added and the mixture extracted with EtOAc. Purification via prep-HPLC gave the title compound. MS (ESI) mass calcd. for C22H₂₄FN₇O, 421.2; m/z found 422.2 [M+H]⁺. ¹H NMR (CD3OD) 7.90-7.73 (m, 3H), 7.34-7.14 (m, 2H), 6.31-6.26 (m, 1H), 4.62-4.41 (m, 1H), 3.74-3.57 (m, 1H), 3.46-3.22 (m, 1H), 3.18-2.93 (m, 1H), 2.40-1.91 (m, 7H), 1.85-1.20 (m, 6H).

Example 171: (±)-(5-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl)(2-(((4-(trifluoromethyl)pyrimidin-2-yl)amino)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to example 170 substituting 2-chloro-4,6-dimethylpyrimidine with 2-chloro-4-(trifluoromethyl)pyrimidine. MS (ESI) mass calcd. for C₂₁H₁₉F₄N₇O, 461.2; m/z found 462.1 [M+H]⁺. 1H NMR (CD3OD): 8.51 (s, 1H), 7.99-7.83 (m, 3H), 7.46-7.16 (m, 2H), 6.88 (d, J=4.9 Hz, 1H), 4.74-4.53 (m, 1H), 3.87-3.66 (m, 1H), 3.34 (s, 1H), 3.30-3.02 (m, 1H), 2.33-2.08 (m, 1H), 1.97-1.32 (m, 6H).

Example 172: (±)-(5-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl)(2-(((6-(trifluoromethyl)pyridin-2-yl)amino)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to example 170 substituting 2-chloro-4,6-dimethylpyrimidine with 2-chloro-6-(trifluoromethyl)pyridine. MS (ESI) mass calcd. for C₂₂H₂₀F₄N₆O, 460.2; m/z found 461.2 [M+H]⁺. 1H NMR (CD3OD): 8.07-7.84 (m, 3H), 7.60-7.22 (m, 3H), 6.90 (d, J=7.2 Hz, 1H), 6.74-6.58 (m, 1H), 4.77-4.58 (m, 1H), 3.90-3.72 (m, 1H), 3.30-3.05 (m, 2H), 2.37-2.12 (m, 1H), 1.99-1.37 (m, 6H).

Example 173: (±)-(3-fluoro-2-methoxyphenyl)(2-(((5-fluoropyridin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 7 substituting 6-methyl-3-(2H-1,2,3-triazol-2-yl)picolinic acid with 3-fluoro-2-methoxybenzoic acid. MS (ESI) mass calcd. for C₂₀H₂₀F₂N₂O₃, 374.1; m/z found 375.1 [M+H]⁺. 1H NMR (CD3OD): 8.01-7.90 (m, 1H), 7.56-7.38 (m, 1H), 7.28-7.06 (m, 2H), 7.02-6.53 (m, 2H), 4.82-4.66 (m, 1H), 4.50-3.73 (m, 6H), 2.85-2.22 (m, 1H), 2.21-1.10 (m, 6H).

Example 174: (±)-(5-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl)(2-((quinoxalin-2-ylamino)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to example 170 substituting 2-chloro-4,6-dimethylpyrimidine with 2-chloroquinoxaline. MS (ESI) mass calcd. for C₂₄H₂₂FN₇O, 443.2; m/z found 444.2 [M+H]⁺.

Example 175: (±)-(2-(((5-fluoropyrimidin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)(6-methyl-3-(pyrimidin-2-yl)pyridin-2-yl)methanone

Prepared analogous to example 98 substituting 3,6′-dimethyl-[2,3′-bipyridine]-2′-carboxylic acid with intermediate A-9. MS (ESI) mass calcd. for C₂₂H₂₁FN₆O₂, 420.2; m/z found 421 [M+H]⁺.

Example 176: (±)-(6-methyl-3-(2H-1,2,3-triazol-2-yl)pyridin-2-yl)(2-(((3-methylpyridin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to example 7 substituting 5-fluoropyridin-2(1H)-one with 3-methylpyridin-2-ol. MS (ESI) mass calcd. for C₂₂H₂₄N₆O₂, 404.2; m/z found 405 [M+H

Example 177: (±)-(2-(((5-fluoropyridin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)(6-methyl-3-(4-methyloxazol-2-yl)pyridin-2-yl)methanone

Prepared analogous to Example 7 substituting 6-methyl-3-(2H-1,2,3-triazol-2-yl)picolinic acid with intermediate A-54. MS (ESI) mass calcd. for C₂₃H₂₃FN₄O₃, 422.2; m/z found 423 [M+H]⁺.

Example 178: (6-methyl-3-(4-methyloxazol-2-yl)pyridin-2-yl)((1S,2R,4R)-2-((pyridin-2-yloxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 1 substituting intermediate A-7 with intermediate A-54. MS (ESI) mass calcd. for C₂₃H₂₄N₄O₃, 404.2; m/z found 405 [M+H]⁺.

Example 179: ((1S,2R,4R)-2-(((5-fluoropyrimidin-2-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)(6-methyl-3-(4-methyloxazol-2-yl)pyridin-2-yl)methanone

Prepared analogous to Example 98 substituting intermediate 3,6′-dimethyl-[2,3′-bipyridine]-2′-carboxylic acid with intermediate A-54. MS (ESI) mass calcd. for C₂₂H₂₂FN₅O₃, 423.2; m/z found 424 [M+H]⁺.

Example 180: (±)-(5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl)(2-(((6-methyl-2-(trifluoromethyl)pyrimidin-4-yl)oxy)methyl)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 13 substituting 2-chloro-4-(trifluoromethyl)pyrimidine with 4-chloro-6-methyl-2-(trifluoromethyl)pyrimidine. MS (ESI) mass calcd. for C₂₃H₂₃F₃N₆O₂, 472.2; m/z found 473.2 [M+H]⁺. ¹H NMR (CDCl₃): 7.88-7.72 (m, 3H), 7.38-7.12 (m, 2H), 6.74-6.70 (s, 0.6H), 6.55-6.50 (s, 0.4H), 4.89-4.75 (m, 1H), 4.30-3.87 (m, 2H), 3.85-3.46 (m, 1H), 2.56-2.49 (m, 3H), 2.46-2.39 (s, 2H), 2.32-1.80 (m, 3H), 1.74-1.11 (m, 5H).

Example 181: (2-(2H-1,2,3-triazol-2-yl)phenyl)((1S,2R,4R)-2-((5-(trifluoromethyl)pyrazin-2-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Step A: (1S,2R,4R)-tert-butyl 2-((5-(trifluoromethyl)pyrazin-2-yl)amino)-7-azabicyclo[2.2.1]heptane-7-carboxylate. To intermediate B-5 (1.6 g, 7.3 mmol) and K₂CO₃ (1.5 g, 10 mmol) in DMF (11 mL) was added 2-chloro-5-(trifluoromethyl)pyrazine (1.1 mL, 8.8 mmol). After heating at 70° C. for 2 h, the mixture was cooled to rt, diluted with EtOAc and H₂O. The aqueous layer was extracted with EtOAc (3×). The combined organics were washed with 4% (aq) and dried (MgSO₄). Purification via silica gel chromatography (0-40% EtOAc in hexanes) gave the title compound (1.8 g, 67%). MS (ESI) mass calcd. for C₁₆H₂₁F₃N₄O₂, 358.2; m/z found 359.2 [M+H]⁺. ¹H NMR (CDCl3): 8.32 (s, 1H), 7.86-7.82 (m, 1H), 5.33 (s, 1H), 4.38-4.15 (m, 2H), 4.10-3.96 (m, 1H), 2.14-1.98 (m, 1H), 1.93-1.67 (m, 2H), 1.61-1.36 (m, 12H).

Step B: (1S,2R,4R)—N-(5-(trifluoromethyl)pyrazin-2-yl)-7-azabicyclo[2.2.1]heptan-2-amine. To the title compound of step A (200 mg, 0.6 mmol) in EtOAc (1 mL) was added 4M HCl in dioxane (3 mL). After 2 h, the reaction was concentrated, neutralized with 5% Na₂CO₃ (aq) and extracted with DCM (2×). The combined organics were dried (Na₂SO₄) to give the title compound of step B that was used without further purification. MS (ESI) mass calcd. for C₁₁H₁₃F₃N₄, 258.1; m/z found 259.1 [M+H]⁺.

Step C: (2-(2H-1,2,3-triazol-2-yl)phenyl)((1S,2R,4R)-2-((5-(trifluoromethyl)pyrazin-2-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)methanone. To the title compound of step B (140 mg, 0.5 mmol) and intermediate A-1 (113 mg, 0.6 mmol) in DMF (4 mL) was added DIPEA (230 μL, 1.4 mmol) and HATU (155 mg, 0.6 mmol). Upon completion of the reaction, purification was performed using Agilent prep method X to give the title compound (172 mg, 74%). MS (ESI) mass calcd. for C₂₀H₁₈F₃N₇O, 429.2; m/z found 430 [M+H]⁺. ¹H NMR (CDCl3): 8.32 (s, 0.3H), 8.17 (s, 0.7H), 7.99-7.89 (m, 1.5H), 7.88-7.77 (m, 1.5H), 7.62-7.30 (m, 4H), 6.24-6.15 (m, 0.3H), 4.86 (s, 0.7H), 4.76 (d, J=5.4 Hz, 0.3H), 4.45-4.23 (m, 1H), 4.08-3.90 (m, 1H), 2.23-1.34 (m, 6H).

Example 182: (±)-((2-(2H-1,2,3-triazol-2-yl)phenyl)(2-((5-(trifluoromethyl)pyrazin-2-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Step A: (±)-tert-butyl 2-((5-(trifluoromethyl)pyrazin-2-yl)amino)-7-azabicyclo[2.2.1]heptane-7-carboxylate. Prepared analogous to Example 181 step A substituting intermediate B-5 with intermediate B-6.

Step B: (±)-N-(5-(trifluoromethyl)pyrazin-2-yl)-7-azabicyclo[2.2.1]heptan-2-amine. Prepared analogous to Example 181 step B substituting (1S,2R,4R)-tert-butyl 2-((5-(trifluoromethyl)pyrazin-2-yl)amino)-7-azabicyclo[2.2.1]heptane-7-carboxylate with (±)-tert-butyl 2-((5-(trifluoromethyl)pyrazin-2-yl)amino)-7-azabicyclo[2.2.1]heptane-7-carboxylate.

Step C: (±)-((2-(2H-1,2,3-triazol-2-yl)phenyl)(2-((5-(trifluoromethyl)pyrazin-2-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)methanone.

To 2-(2H-1,2,3-triazol-2-yl)benzoic acid (125 mg, 0.6 mmol) and DMF (4 mL) was added (i-Pr)₂NEt (0.23 mL, 1.3 mmol) and HBTU (155 mg, 0.6 mmol). After 10 min, the title compound from step B (146 mg. 0.4 mmol) was added. After stirring overnight at rt, saturated NaHCO₃ (aq.) was added and the mixture extracted with EtOAc (3×). The combined organics were dried (MgSO₄) and concentrated. Purification via preparative HPLC gave the title compound (89 mg, 47%) as a beige solid. MS (ESI) mass calcd. for C₂₀H₁₈F₃N₇O, 429.2; m/z found 430 [M+H]⁺. ¹H NMR (DMSO-D₆): 8.47 (s, 0.3H), 8.24 (s, 0.7H), 8.14-8.05 (m, 2.2H), 8.02 (s, 0.7H), 7.85 (d, J=7.2 Hz, 1.3H), 7.72-7.55 (m, 1.7H), 7.49-7.34 (m, 1.4H), 7.13 (t, J=7.4 Hz, 0.7H), 4.58 (t, J=4.3 Hz, 0.7H), 4.44 (d, J=4.7 Hz, 0.3H), 4.04-3.93 (m, 0.3H), 3.82 (t, J=4.1 Hz, 0.3H), 3.79-3.70 (m, 0.7H), 3.54 (d, J=4.8 Hz, 0.7H), 2.07-1.90 (m, 1H), 1.85-1.07 (m, 5H).

Example 183a: (2-(2H-1,2,3-triazol-2-yl)phenyl)((1S,2R,4R)-2-((5-(trifluoromethyl)pyrazin-2-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

And Example 183b: (2-(2H-1,2,3-triazol-2-yl)phenyl)((1R,2S,4S)-2-((5-trifluoromethyl)pyrazin-2-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

The title compounds were obtained by chiral SFC (CHIRALPAK OD-H 5 μM 250×20 mm) resolution of Example 182 (81 mg) using 70% CO₂/30% EtOH as the mobile phase to give enantiomer A (37 mg, 1st eluting enantiomer, example 183a) and enantiomer B (38 mg, 2^(nd) eluting enantiomer, example 183b). Example 183a: >98% single enantiomer, 2.45 min retention time; Example 183b>98% single enantiomer, 3.33 min retention time.

Example 183a: Enantiomer A: MS (ESI) mass calcd. for C₂₀H₁₈F₃N₇O, 429.2; m/z found 430 [M+H]⁺.

Example 183b: Enantiomer B: MS (ESI) mass calcd. for C₂₀H₁₈F₃N₇O, 429.2; m/z found 430 [M+H]⁺.

Example 184: (±)-(5-methyl-3-(2H-1,2,3-triazol-2-yl)pyridin-2-yl)(2-((5-(trifluoromethyl)pyrazin-2-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 182 substituting intermediate A-1 with intermediate A-19 and HBTU with HATU. MS (ESI) mass calcd. for C₂₀H₁₉F₃N₈O, 444.2; m/z found 445.1 [M+H]⁺.

Example 185: (±)-(5-methyl-3-(1H-1,2,3-triazol-1-yl)pyridin-2-yl)(2-((5-(trifluoromethyl)pyrazin-2-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 184 substituting intermediate A-19 with intermediate A-20. MS (ESI) mass calcd. for C₂₀H₁₉F₃N₈O, 444.2; m/z found 445.1 [M+H]⁺. HPLC R_(t)=1.13.

Example 186: (±)-(6-methyl-3-(2H-1,2,3-triazol-2-yl)pyridin-2-yl)(2-((5-(trifluoromethyl)pyrazin-2-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 184 substituting intermediate A-19 with intermediate A-21. MS (ESI) mass calcd. for C₂₀H₁₉F₃N₈O, 444.2; m/z found 445.1 [M+H]⁺. ¹H NMR (CDCl₃): 8.36-8.32 (s, 0.2H), 8.27-8.23 (s, 0.8H), 8.22-8.18 (d, J=8.4 Hz, 0.2H), 8.13-8.08 (d, J=8.3 Hz, 0.8H), 7.93-7.84 (m, 2H), 7.79-7.75 (m, 0.8H), 7.40-7.36 (d, J=8.4 Hz, 0.2H), 7.36-7.31 (d, J=8.4 Hz, 0.8H), 7.26-7.22 (m, 0.2H), 6.26-6.19 (d, J=8.5 Hz, 0.2H), 4.96-4.86 (t, J=4.8 Hz, 0.8H), 4.83-4.75 (d, J=5.4 Hz, 0.2H), 4.36-4.19 (m, 1H), 4.13-3.92 (d, J=5.0 Hz, 1H), 2.69-2.56 (m, 3H), 2.29-2.14 (dd, J=13.1, 7.5 Hz, 1H), 2.14-1.87 (m, 2H), 1.81-1.78 (m, 1H), 1.63-1.56 (m, 2H).

Example 187: (±)-(6-methyl-3-(2H-1,2,3-triazol-2-yl)pyridin-2-yl)(2-((5-(trifluoromethyl)pyridin-2-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Step A: (±)-tert-butyl 2-((5-(trifluoromethyl)pyridin-2-yl)amino)-7-azabicyclo[2.2.1]heptane-7-carboxylate. To intermediate B-6 (150 mg, 0.7 mmol) in DMSO (10 mL) was added DIPEA (244 μL, 1.4 mmol) and 2-chloro-5-(trifluoromethyl)pyridine (170 μL, 1.4 mmol). After heating at 100° C. for 4 h, the mixture was cooled to rt and saturated NaHCO₃ (aq) was added. The mixture was extracted with DCM (3×). The combined organics were washed with brine and dried (MgSO₄). Purification via silica gel chromatography (0-13% EtOAc in heptanes) gave the title compound. MS (ESI) mass calcd. for C₁₇H₂₂F₃N₇O₂, 357.2; m/z found 358.0 [M+H]⁺.

Step B: (±)-N-(5-(trifluoromethyl)pyridin-2-yl)-7-azabicyclo[2.2.1]heptan-2-amine hydrochloride. To the title compound from step A (262 mg, 0.7 mmol) in 1,4-dioxane (10 mL) was added 6N HCl in iPrOH (700 μL). The reaction was heated to 70° C. for 2 h, cooled to rt, concentrated and used without further purification in subsequent steps.

Step C: (±)-(6-methyl-3-(2H-1,2,3-triazol-2-yl)pyridin-2-yl)(2-((5-(trifluoromethyl)pyridin-2-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)methanone.

Prepared analogous to Example 182 substituting intermediate A-1 with intermediate A-21 and (±)-N-(5-(trifluoromethyl)pyrazin-2-yl)-7-azabicyclo[2.2.1]heptan-2-amine with the title compound of step B. MP=193.9° C. ¹H NMR (DMSO-D₆): 8.38 (s, 0.3H), 8.24-8.16 (m, 1H), 8.15-8.11 (m, 2H), 8.05 (d, J=8.3 Hz, 0.7H), 7.69 (dd, J=8.9, 2.3 Hz, 0.3H), 7.63 (dd, J=8.9, 2.4 Hz, 0.7H), 7.57 (d, J=8.4 Hz, 0.3H), 7.37 (d, J=8.4 Hz, 0.7H), 7.33 (d, J=5.8 Hz, 0.7H), 7.14 (d, J=4.5 Hz, 0.3H), 6.75 (d, J=8.9 Hz, 0.3H), 6.61 (d, J=8.9 Hz, 0.7H), 4.60 (t, J=4.5 Hz, 0.7H), 4.51 (d, J=4.8 Hz, 0.3H), 3.99-3.90 (m, 0.6H), 3.89-3.77 (m, 1.4H), 2.60 (s, 0.9H), 2.23 (s, 2.1H), 1.99 (dd, J=12.6, 7.6 Hz, 1H), 1.83-1.21 (m, 5H).

Example 188: (±)-(5-methyl-3-(2H-1,2,3-triazol-2-yl)pyridin-2-yl)(2-((5-(trifluoromethyl)pyridin-2-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 187 substituting intermediate A-21 with intermediate A-19. MS (ESI) mass calcd. for C₂₁H₂₀F₃N₇O, 443.2; m/z found 444.1 [M+H]⁺. ¹H NMR (CDCl₃): 8.49-8.44 (dd, J=1.9, 0.9 Hz, 0.2H), 8.41-8.32 (m, 1H), 8.28-8.21 (m, 0.8H), 8.18-8.11 (m, 0.2H), 8.06-7.98 (m, 0.8H), 7.94-7.86 (m, 2H), 7.60-7.53 (dd, J=8.8, 2.4 Hz, 0.2H), 7.45-7.35 (dd, J=8.9, 2.4 Hz, 0.8H), 6.71-6.59 (d, J=8.7 Hz, 0.8H), 6.45-6.37 (d, J=8.8 Hz, 0.2H), 6.27-6.17 (d, J=8.8 Hz, 0.8H), 5.82-5.72 (m, 0.2H), 4.95-4.84 (t, J=4.6 Hz, 0.8H), 4.82-4.74 (d, J=5.2 Hz, 0.2H), 4.36-4.18 (m, 1H), 4.08-3.97 (m, 1H), 2.51-2.47 (s, 0.7H), 2.45-2.41 (m, 2.3H), 2.22-2.14 (dd, J=13.0, 7.7 Hz, 0.8H), 2.11-1.90 (m, 2.2H), 1.82-1.40 (m, 3H).

Example 189: (±)-(6-methyl-2-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)(2-((5-(trifluoromethyl)pyridin-2-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 187 substituting intermediate A-21 with intermediate A-3. MS (ESI) mass calcd. for C₂₁H₂₀F₃N₇O, 443.2; m/z found 444.1 [M+H]⁺. ¹H NMR (CDCl₃): 8.40-8.33 (s, 0.4H), 8.26-8.19 (d, J=2.0 Hz, 0.6H), 7.98-7.88 (m, 2H), 7.78-7.71 (d, J=7.7 Hz, 0.4H), 7.64-7.55 (m, 1H), 7.41-7.27 (m, 1.6H), 7.20-7.08 (m, 0.7H), 6.43-6.35 (d, J=8.8 Hz, 0.3H), 6.13-6.01 (d, J=8.7 Hz, 0.7H), 5.74-5.56 (m, 0.3H), 4.90-4.81 (m, 0.7H), 4.78-4.71 (d, J=5.3 Hz, 0.3H), 4.38-4.14 (m, 1H), 3.99-3.85 (m, 1H), 2.78-2.55 (m, 3H), 2.24-2.10 (dd, J=13.2, 7.9 Hz, 1H), 2.08-1.39 (m, 5H).

Example 190: (±)-(6-methyl-2-(1H-1,2,3-triazol-1-yl)pyridin-3-yl)(2-((5-(trifluoromethyl)pyridin-2-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 187 substituting intermediate A-21 with intermediate A-4. MS (ESI) mass calcd. for C₂₁H₂₀F₃N₇O, 443.2; m/z found 444.1 [M+H]⁺. ¹H NMR (CDCl₃): 8.50-8.46 (m, 0.6H), 8.37-8.34 (d, J=1.2 Hz, 0.4H), 8.34-8.31 (s, 0.6H), 8.24-8.17 (s, 0.4H), 7.90-7.84 (m, 1H), 7.75-7.69 (d, J=7.7 Hz, 0.6H), 7.65-7.60 (d, J=7.8 Hz, 0.4H), 7.55-7.47 (dd, J=8.7, 2.4 Hz, 0.7H), 7.36-7.27 (m, 1.3H), 7.22-7.14 (m, 0.4H), 6.94-6.83 (d, J=8.7 Hz, 0.6H), 6.29-6.11 (d, J=8.9 Hz, 1H), 4.91-4.74 (d, J=5.3 Hz, 1H), 4.55-4.28 (m, 1H), 4.04-3.90 (m, 1H), 2.66-2.62 (s, 1.9H), 2.59-2.55 (s, 1.1H), 2.23-2.15 (dd, J=13.1, 8.1 Hz, 0.5H), 2.06-1.79 (m, 2.5H), 1.77-1.68 (m, 1H), 1.55-1.47 (m, 2H).

Example 191: (±)-(4-methoxy-2-(2H-1,2,3-triazol-2-yl)phenyl)(2-((5-(trifluoromethyl)pyridin-2-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 187 substituting intermediate A-21 with intermediate A-5. MS (ESI) mass calcd. for C₂₂H₂₁F₃N₆O₂, 458.2; m/z found 459.1 [M+H]⁺. ¹H NMR (CDCl₃): 8.38-8.32 (s, 0.3H), 8.26-8.19 (s, 0.7H), 7.93-7.87 (s, 1.3H), 7.87-7.80 (s, 0.7H), 7.60-7.53 (m, 0.4H), 7.49-7.43 (d, J=2.5 Hz, 0.4H), 7.40-7.26 (m, 2.7H), 7.00-6.93 (dd, J=8.5, 2.5 Hz, 0.4H), 6.90-6.80 (d, J=8.4 Hz, 0.7H), 6.43-6.35 (d, J=8.7 Hz, 0.4H), 6.12-6.04 (d, J=8.8 Hz, 0.7H), 5.77-5.67 (m, 0.3H), 4.84-4.79 (m, 0.7H), 4.74-4.68 (m, 0.3H), 4.36-4.15 (m, 1H), 4.02-3.95 (m, 1H), 3.94-3.87 (s, 1H), 3.87-3.81 (s, 2H), 2.20-2.11 (dd, J=13.0, 8.0 Hz, 0.7H), 2.07-1.99 (dd, J=12.9, 7.6 Hz, 0.3H), 1.99-1.83 (s, 2H), 1.79-1.34 (m, 3H).

Example 192: (±)-(3-fluoro-2-(pyrimidin-2-yl)phenyl)(2-((5-(trifluoromethyl)pyridin-2-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 187 substituting intermediate A-21 with intermediate A-6. MS (ESI) mass calcd. for C₂₃H₁₉F₄N₅O, 457.2; m/z found 458.1 [M+H]⁺. ¹H NMR (CDCl₃): 8.91-8.76 (m, 2H), 8.36-8.18 (m, 1H), 7.68-7.52 (m, 1H), 7.40-7.27 (m, 3H), 7.24-7.14 (m, 2H), 6.29-6.15 (m, 1H), 4.78-4.66 (t, J=4.9 Hz, 1H), 4.44-4.30 (m, 1H), 4.16-4.02 (d, J=5.0 Hz, 1H), 2.19-2.11 (dd, J=12.9, 8.2 Hz, 1H), 2.08-1.97 (m, 1H), 1.97-1.85 (m, 1H), 1.77-1.60 (m, 2H), 1.54-1.49 (m, 1H).

Example 193: (±)-((3-fluoro-2-methoxyphenyl)(2-((5-(trifluoromethyl)pyridin-2-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 187 substituting intermediate A-21 with 3-fluoro-2-methoxybenzoic acid. MS (ESI) mass calcd. for C₂₀H₁₉F₄N₃O₂, 409.1; m/z found 410.4 [M+H]⁺. ¹H NMR (MeOD): 8.39 (s, 0.3H), 8.18 (s, 0.7H), 7.69 (dd, J=8.9, 2.3 Hz, 0.3H), 7.60 (dd, J=8.9, 2.4 Hz, 0.7H), 7.36 (ddd, J=11.7, 7.6, 2.1 Hz, 0.3H), 7.30-7.05 (m, 2.3H), 7.01 (d, J=7.6 Hz, 0.7H), 6.85-6.73 (m, 0.7H), 6.68 (d, J=8.8 Hz, 0.3H), 6.59 (d, J=8.9 Hz, 0.7H), 4.66 (br s, 0.7H), 4.54 (d, J=4.8 Hz, 0.3H), 4.00-3.90 (m, 0.3H), 3.89-3.77 (m, 3.7H), 3.75 (t, J=4.3 Hz, 0.3H), 3.64 (br s, 0.7H), 2.08-1.91 (m, 1H), 1.80-1.37 (m, 5H).

Example 194: (±)-(3-ethoxy-6-methylpyridin-2-yl)(2-((5-(trifluoromethyl)pyridin-2-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 187 substituting intermediate A-21 with intermediate A-8. MP=147° C. ¹H NMR (DMSO-D₆): 8.38 (s, 0.3H), 8.16 (s, 0.7H), 7.68 (dd, J=8.9, 2.3 Hz, 0.3H), 7.59 (dd, J=8.9, 2.4 Hz, 0.7H), 7.46 (d, J=8.6 Hz, 0.3H), 7.36-7.18 (m, 2H), 7.05 (d, J=8.6 Hz, 0.7H), 6.71 (d, J=8.9 Hz, 0.3H), 6.57 (d, J=8.9 Hz, 0.7H), 4.65 (br s, 0.7H), 4.55 (d, J=2.8 Hz, 0.3H), 4.13-3.84 (m, 2.3H), 3.83-3.72 (m, 0.7H), 3.67 (d, J=3.5 Hz, 1H), 2.41 (s, 0.9H), 2.16 (s, 2.1H), 2.04-1.91 (m, 1H), 1.80-1.37 (m, 5H), 1.31-1.19 (m, 3H).

Example 195: (±)-(6-methyl-3-(pyrimidin-2-yl)pyridin-2-yl)(2-((5-(trifluoromethyl)pyridin-2-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 187 substituting intermediate A-21 with intermediate A-9. MS (ESI) mass calcd. for C₂₃H₂₁F₃N₆O, 454.2; m/z found 455 [M+H]⁺. ¹H NMR (DMSO-D₆): 8.95-8.81 (m, 2H), 8.37 (s, 0.3H), 8.32 (d, J=8.0 Hz, 0.3H), 8.25-8.13 (m, 1.4H), 7.68 (dd, J=8.8, 2.1 Hz, 0.3H), 7.60 (dd, J=8.9, 2.2 Hz, 0.7H), 7.52-7.39 (m, 2H), 7.30 (d, J=8.1 Hz, 0.7H), 7.25 (d, J=3.7 Hz, 0.3H), 6.75 (d, J=8.8 Hz, 0.3H), 6.54 (d, J=8.9 Hz, 0.7H), 4.61 (t, J=4.2 Hz, 0.7H), 4.51 (d, J=4.2 Hz, 0.3H), 4.01-3.82 (m, 2H), 2.58 (s, 0.9H), 2.24 (s, 2.1H), 2.07-1.95 (m, 1H), 1.86-1.32 (m, 5H).

Example 196: (±)-(2-(2H-1,2,3-triazol-2-yl)phenyl)(2-((5-(trifluoromethyl)pyridin-2-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 187 substituting intermediate A-21 with intermediate A-1. MS (ESI) mass calcd. for C₂₁H₁₉F₃N₆O, 428.2; m/z found 409.2 [M+H]⁺. ¹H NMR (MeOD): 8.38 (s, 0.3H), 8.16 (s, 0.7H), 8.08 (s, 2H), 7.85 (d, J=7.2 Hz, 0.3H), 7.74-7.53 (m, 3H), 7.46-7.35 (m, 1.3H), 7.31 (d, J=6.1 Hz, 0.7H), 7.14 (t, J=7.5 Hz, 0.7H), 6.68 (d, J=8.9 Hz, 0.3H), 6.62 (d, J=8.9 Hz, 0.7H), 4.57 (t, J=4.5 Hz, 0.7H), 4.41 (d, J=4.8 Hz, 0.3H), 4.04-3.95 (m, 0.3H), 3.88-3.76 (m, 1H), 3.55 (br s, 0.7H), 1.97 (dd, J=12.7, 8.0 Hz, 1H), 1.79-1.23 (m, 5H).

Example 197: (±)-(2-((4,6-dimethylpyrimidin-2-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)(5-fluoro-2-2H-1,2,3-triazol-2-yl)phenyl)methanone

Step A: (±)-tert-butyl 2-((4,6-dimethylpyrimidin-2-yl)amino)-7-azabicyclo[2.2.1]heptane-7-carboxylate. To a microwave vial was weighed intermediate B-6 (210 mg, 1 mmol), 2-chloro-4,6-dimethylpyrimidine (212 mg, 1.5 mmol), sodium tert-butoxide (142 mg, 1.5 mmol), Pd(dba)₂ (28 mg, 5 mol %), Ctc-Q-Phos (44 mg, 10 mol). The vial was capped, evacuated and refilled with N₂ (2×). Then PhCH₃ (1 mL) was added and the reaction was heated at 125° C. for 4 h. The reaction allowed to cool to rt, applied directly purified via silica gel chromatography 1-7% 2M NH3/MeOH in DCM to give P1 (125 mg, 40%). MS (ESI) mass calcd. for C₁₇H₂₆N₄O₂, 318.2; m/z found 319.3 [M+H]⁺. ¹H NMR (CDCl₃): 6.31 (s, 1H), 5.18-4.94 (m, 1H), 4.35-4.13 (m, 2H), 4.08 (td, J=7.9, 3.2 Hz, 1H), 2.27 (s, 6H), 1.97 (dd, J=12.9, 7.8 Hz, 1H), 1.82-1.62 (m, 2H), 1.62-1.30 (m, 12H).

Step B: (±)-N-(4,6-dimethylpyrimidin-2-yl)-7-azabicyclo[2.2.1]heptan-2-amine. To the title compound of step A (125 mg, 0.4 mmol) in DCM (3 mL) was added TFA (3 mL). After starting material was consumed, the reaction was concentrated, neutralized with 5% Na₂CO₃ and extracted with DCM. The combined organics were dried (Na₂SO₄) to give the title compound that was used in subsequent reactions without further purification. MS (ESI) mass calcd. for C₁₂H₁₈N₄, 218.2; m/z found 219.2 [M+H]⁺.

Step C: (±)-(2-((4,6-dimethylpyrimidin-2-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)(5-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone. Prepared analogous to Example 181 substituting intermediate A-1 with intermediate A-10 and (1 S,2R,4R)—N-(5-(trifluoromethyl)pyrazin-2-yl)-7-azabicyclo[2.2.1]heptan-2-amine with the title compound of step B. MS (ESI) mass calcd. for C₂₁H₂₂FN₇O, 407.2; m/z found 408.2 [M+H]⁺. ¹H NMR (CDCl₃): 8.23-7.67 (m, 2.5H), 7.54-6.93 (m, 2.5H), 6.40-6.19 (m, 1H), 4.89-4.65 (m, 1H), 4.41-3.66 (m, 2H), 2.39-1.34 (m, 12H).

Example 198: (±)-(2-((4,6-dimethylpyrimidin-2-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)(2-fluoro-6-(2H-1,2,3-triazol-2-yl)phenyl)methanone

Prepared analogous to Example 197 substituting intermediate A-10 with intermediate A-11. MS (ESI) mass calcd. for C₂₁H₂₂FN₇O, 407.2; m/z found 408.2 [M+H]⁺.

Example 199: (±)-(2-((4,6-dimethylpyrimidin-2-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)(4-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone

Prepared analogous to Example 197 substituting intermediate A-10 with intermediate A-12. MS (ESI) mass calcd. for C₂₁H₂₂FN₇O, 407.2; m/z found 408.2 [M+H]⁺. ¹H NMR (MeOD): 8.23-7.33 (m, 4H), 7.22-6.75 (m, 1H), 6.42-6.21 (m, 1H), 4.91-4.73 (m, 1H), 4.44-4.01 (m, 1H), 3.97-3.71 (m, 1H), 2.41-1.30 (m, 12H).

Example 200: (±)-(2-((4,6-dimethylpyrimidin-2-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)(6-methyl-3-(pyrimidin-2-yl)pyridin-2-yl)methanone

Prepared analogous to Example 187 substituting 2-chloro-5-(trifluoromethyl)pyridine with 2-chloro-4,6-dimethylpyrimidine and intermediate A-21 with intermediate A-9. MS (ESI) mass calcd. for C₂₃H₂₅N70, 415.2; m/z found 416 [M+H]⁺. ¹H NMR (DMSO-D₆): 9.05 (d, J=4.9 Hz, 0.6H), 8.90 (d, J=4.9 Hz, 1.4H), 8.37 (d, J=8.1 Hz, 0.3H), 8.28 (d, J=8.0 Hz, 0.7H), 7.57-7.45 (m, 1.3H), 7.41 (d, J=8.1 Hz, 0.7H), 7.09 (d, J=7.8 Hz, 0.7H), 6.46 (s, 0.3H), 6.43-6.29 (m, 1H), 4.62 (br s, 0.7H), 4.51 (d, J=4.4 Hz, 0.3H), 4.15-3.97 (m, 1H), 3.97-3.92 (m, 0.3H), 3.89 (d, J=3.7 Hz, 0.7H), 2.59 (s, 0.9H), 2.50 (s, 2.1H), 2.26 (s, 1.8H), 2.14 (s, 4.2H), 2.05 (dd, J=12.5, 7.6 Hz, 1H), 1.99-1.37 (m, 5H).

Example 201: (±)-(2-((4,6-dimethylpyrimidin-2-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)(6-methyl-3-(2H-1,2,3-triazol-2-yl)pyridin-2-yl)methanone

Prepared analogous to Example 200 substituting intermediate A-9 with intermediate A-21. MP=171.9° C. 1H NMR (DMSO-D₆): 8.28-8.17 (m, 1.2H), 8.17-8.09 (m, 1.8H), 7.57 (d, J=8.4 Hz, 0.4H), 7.46 (d, J=8.4 Hz, 0.6H), 6.89 (d, J=7.0 Hz, 0.6H), 6.46 (s, 0.4H), 6.42 (d, J=7.5 Hz, 0.4H), 6.35 (s, 0.6H), 4.59 (t, J=4.2 Hz, 0.6H), 4.50 (d, J=4.9 Hz, 0.4H), 4.08 (td, J=7.8, 3.0 Hz, 0.4H), 4.00-3.86 (m, 1.6H), 2.60 (s, 1.2H), 2.45 (s, 1.8H), 2.26 (s, 2.4H), 2.15 (s, 3.6H), 1.97 (ddd, J=16.3, 12.6, 7.9 Hz, 1H), 1.83-1.35 (m, 5H).

Example 202: (±)-(2-(2H-1,2,3-triazol-2-yl)phenyl)(2-((4,6-dimethylpyrimidin-2-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 200 substituting intermediate A-9 with intermediate A-1. MP=154.2° C. 1H NMR (DMSO-D₆): 8.12 (s, 1H), 8.07 (s, 1H), 7.85 (d, J=7.7 Hz, 0.5H), 7.77 (d, J=6.8 Hz, 0.5H), 7.72-7.61 (m, 1H), 7.58 (dd, J=10.7, 4.2 Hz, 0.5H), 7.49-7.39 (m, 1H), 7.15 (t, J=7.5 Hz, 0.5H), 6.99 (d, J=6.1 Hz, 0.5H), 6.87 (br s, 0.5H), 6.43 (s, 0.5H), 6.33 (s, 0.5H), 4.51 (t, J=4.1 Hz, 0.5H), 4.37 (d, J=3.9 Hz, 0.5H), 4.12-3.97 (m, 0.5H), 3.88-3.72 (m, 1H), 3.68 (d, J=4.4 Hz, 0.5H), 2.24 (s, 3H), 2.15 (s, 3H), 1.97-1.21 (m, 6H).

Example 203: (±)-(2-((4,6-dimethylpyrimidin-2-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)(3-ethoxy-6-methylpyridin-2-yl)methanone

Prepared analogous to Example 200 substituting intermediate A-9 with intermediate A-8. MS (ESI) mass calcd. for C₂₁H₂₇N₅O₂, 381.2; m/z found 382.5 [M+H]⁺. MP=137.8° C. ¹H NMR (DMSO-D₆): 7.20-7.01 (m, 2H), 6.45 (d, J=8.5 Hz, 0.7H), 6.31 (s, 0.3H), 6.24 (s, 0.7H), 5.31 (d, J=8.6 Hz, 0.3H), 4.91 (t, J=4.5 Hz, 0.7H), 4.80 (d, J=5.1 Hz, 0.3H), 4.32-4.14 (m, 1.7H), 4.14-3.98 (m, 1.3H), 3.80 (t, J=4.7 Hz, 0.3H), 3.75 (d, J=4.6 Hz, 0.7H), 2.53 (s, 2.1H), 2.49 (s, 0.9H), 2.26 (s, 1.8H), 2.22 (s, 4.2H), 2.20-2.08 (m, 1H), 2.05-1.49 (m, 5H), 1.48-1.40 (m, 3H).

Example 204: (±)-(2-(2H-1,2,3-triazol-2-yl)phenyl)(2-(quinoxalin-2-ylamino)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Step A: (±)-tert-butyl 2-(quinoxalin-2-ylamino)-7-azabicyclo[2.2.1]heptane-7-carboxylate. To intermediate B-6 (500 mg, 2.4 mmol) in dry DMA (7 mL) was added K₂CO₃ (650 mg, 4.7 mmol) and 2-chloroquinoxaline (580 mg, 3.5 mmol). After heating at 80° C. for 48 h, the mixture was cooled to rt and saturated NaHCO₃ (aq) was added. The mixture was extracted with EtOAc (3×). The combined organics were washed with brine and dried (MgSO₄). Purification via silica gel chromatography (0-25% EtOAc in heptanes) gave the title compound. MS (ESI) mass calcd. for C₁₉H₂₄N₄O₂, 340.2; m/z found 341.0 [M+H]⁺.

Step B: N-((±)-7-azabicyclo[2.2.1]heptan-2-yl)quinoxalin-2-amine hydrochloride. To the title compound from step A (343 mg, 1 mmol) in 1,4-dioxane (10 mL) was added 6N HCl in iPrOH (1 mL). The reaction was heated to 70° C. for 2 h, cooled to rt, concentrated and used without further purification in subsequent steps.

Step C: (±)-(2-(2H-1,2,3-triazol-2-yl)phenyl)(2-(quinoxalin-2-ylamino)-7-azabicyclo[2.2.1]heptan-7-yl)methanone. Prepared analogous to Example 187 substituting intermediate A-21 with intermediate A-1 and (±)-N-(5-(trifluoromethyl)pyridin-2-yl)-7-azabicyclo[2.2.1]heptan-2-amine hydrochloride with the title compound from step B. MS (ESI) mass calcd. for C₂₃H₂₁N70, 411.2; m/z found 412 [M+H]⁺. ¹H NMR (DMSO-D₆): 8.38 (s, 0.3H), 8.31 (s, 0.7H), 8.08 (s, 2H), 7.88-7.73 (m, 1.3H), 7.72-7.20 (m, 7H), 7.14-7.04 (m, 0.7H), 4.60 (t, J=4.4 Hz, 0.7H), 4.54 (d, J=4.7 Hz, 0.3H), 4.15-4.03 (m, 0.3H), 3.97-3.87 (m, 0.7H), 3.82 (t, J=3.9 Hz, 0.3H), 3.65 (d, J=3.2 Hz, 0.7H), 2.12-1.96 (m, 1H), 1.84-1.28 (m, 5H).

Example 205: (±)-(6-methyl-3-(2H-1,2,3-triazol-2-yl)pyridin-2-yl)(2-(quinoxalin-2-ylamino)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 204 substituting with intermediate A-1 with intermediate A-21. MP=260.8° C. ¹H NMR (DMSO-D₆): 8.44 (s, 0.3H), 8.32 (s, 0.7H), 8.19 (d, J=8.4 Hz, 0.3H), 8.13 (s, 2H), 7.96 (d, J=8.3 Hz, 0.7H), 7.83-7.72 (m, 1H), 7.68-7.27 (m, 4.3H), 7.19 (d, J=8.4 Hz, 0.7H), 4.64 (br s, 1H), 4.06-3.86 (m, 2H), 2.61 (s, 0.9H), 2.09 (s, 2.1H), 2.06-1.99 (m, 1H), 1.88-1.62 (m, 2H), 1.62-1.38 (m, 3H).

Example 206: (±)-(3-fluoro-2-methoxyphenyl)(2-(quinoxalin-2-ylamino)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 204 substituting intermediate A-1 with 3-fluoro-2-methoxybenzoic acid. MP=179.2° C. ¹H NMR (DMSO-D₆): 8.38 (s, 0.3H), 8.27 (s, 0.7H), 7.80 (d, J=8.0 Hz, 0.3H), 7.73 (d, J=8.0 Hz, 0.7H), 7.65-7.52 (m, 1.4H), 7.52-7.28 (m, 2.7H), 7.28-7.15 (m, 0.7H), 7.09 (d, J=7.6 Hz, 0.7H), 6.96 (ddd, J=11.7, 8.2, 1.4 Hz, 0.7H), 6.75 (td, J=7.9, 4.8 Hz, 0.7H), 4.75-4.63 (m, 1H), 4.11-4.01 (m, 0.4H), 3.99-3.90 (m, 0.7H), 3.86 (br s, 0.9H), 3.83-3.73 (m, 2.1H), 2.06 (dt, J=16.7, 8.4 Hz, 1H), 1.87-1.45 (m, 6H).

Example 207: (±)-(3-ethoxy-6-methylpyridin-2-yl)(2-(quinoxalin-2-ylamino)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 204 substituting with intermediate A-1 with intermediate A-8. MS (ESI) mass calcd. for C₂₃H₂₅N₅O₂, 403.2; m/z found 404 [M+H]⁺. MP=184.9 C. ¹H NMR (DMSO-D₆): 8.41 (s, 0.3H), 8.26 (s, 0.7H), 7.79 (d, J=8.1 Hz, 0.3H), 7.72 (d, J=8.0 Hz, 0.7H), 7.64-7.53 (m, 1.7H), 7.50-7.22 (m, 2.9H), 7.18 (d, J=8.6 Hz, 0.7H), 6.86 (d, J=8.6 Hz, 0.7H), 4.68 (br s, 1H), 4.12-3.83 (m, 3H), 3.79 (d, J=4.1 Hz, 0.7H), 3.71 (br s, 0.3H), 2.41 (s, 0.9H), 2.11-1.96 (m, 3.1H), 1.89-1.42 (m, 5H), 1.25 (t, J=6.9 Hz, 3H).

Example 208: (±)-(6-methyl-3-(pyrimidin-2-yl)pyridin-2-yl)(2-(quinoxalin-2-ylamino)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 204 substituting with intermediate A-1 with intermediate A-9. MS (ESI) mass calcd. for C₂₅H₂₃N70, 437.2; m/z found 438 [M+H]⁺. ¹H NMR (DMSO-D₆): 8.93-8.82 (m, 2H), 8.46 (s, 0.3H), 8.33 (d, J=8.1 Hz, 0.3H), 8.27 (s, 0.7H), 8.14 (d, J=8.0 Hz, 0.7H), 7.81-7.26 (m, 6.3H), 7.17 (d, J=8.1 Hz, 0.7H), 4.66 (br s, 1H), 4.06-3.94 (m, 2H), 2.60 (s, 0.9H), 2.13-2.01 (m, 3.1H), 1.92-1.36 (m, 5H).

Example 209: (±)-(2-(2H-1,2,3-triazol-2-yl)phenyl)(2-((6-(trifluoromethyl)pyridin-2-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Step A: (±)-tert-butyl-2-((6-(trifluoromethyl)pyridin-2-yl)amino)-7-azabicyclo[2.2.1]heptane-7-carboxylate. To 2-chloro-6-(trifluoromethyl)pyridine (113 mg, 0.6 mmol) in THF (3 mL) was added sodium tert-butoxide (120 mg, 1.2 mmol), Xanphos (26 mg, 7 mol %) and Pd₂(dba)₃ (23 mg, 4 mol %) at rt while N₂ was bubbled through the solution. After 10 minutes, intermediate B-6 (132 mg, 0.6 mmol) was added. The reaction mixture was heated at 90° C. for 3 h. After allowing to cool to rt, saturated NaHCO₃ (aq) the mixture extracted with EtOAc (2×). The combined organics were dried (MgSO₄). Purification via silica gel chromatography (0-7% EtOAc in heptane) gave the title compound. MS (ESI) mass calcd. for C₁₇H₂₂F₃N₃O₂, 357.2; m/z found 358.4 [M+H]⁺.

Step B: (±)-N-(6-(trifluoromethyl)pyridin-2-yl)-7-azabicyclo[2.2.1]heptan-2-amine hydrochloride. Prepared analogous to Example 204 substituting (±)-tert-butyl 2-(quinoxalin-2-ylamino)-7-azabicyclo[2.2.1]heptane-7-carboxylate with the title compound of step A.

Step C: (±)-tert-butyl-2-((6-(trifluoromethyl)pyridin-2-yl)amino)-7-azabicyclo[2.2.1]heptane-7-carboxylate. Prepared analogous to Example 204 substituting N-((±)-7-azabicyclo[2.2.1]heptan-2-yl)quinoxalin-2-amine hydrochloride with the title compound of step B. MS (ESI) mass calcd. for C₂₁H₁₉F₃N₆O, 428.2; m/z found 429. [M+H]⁺. MP=96.8° C. ¹H NMR (DMSO-D₆): 8.07 (s, 2H), 7.85 (d, J=7.9 Hz, 0.3H), 7.74-7.51 (m, 2.7H), 7.46-7.36 (m, 1.3H), 7.17-6.94 (m, 2H), 6.86 (d, J=7.2 Hz, 0.7H), 6.82 (d, J=8.6 Hz, 0.3H), 6.74 (d, J=8.4 Hz, 0.7H), 4.55 (t, J=4.5 Hz, 0.7H), 4.41 (d, J=4.6 Hz, 0.3H), 3.94-3.84 (m, 0.3H), 3.84-3.71 (m, 1H), 3.61 (d, J=4.6 Hz, 0.7H), 1.96 (dd, J=12.6, 8.0 Hz, 1H), 1.80-1.21 (m, 5H).

Example 210: (±)-((2-(2H-1,2,3-triazol-2-yl)phenyl)(2-((4-(trifluoromethyl)pyridin-2-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 209 substituting 2-chloro-6-(trifluoromethyl)pyridine with 2-chloro-4-(trifluoromethyl)pyridine. MP=153.5° C. MS (ESI) mass calcd. for C₂₁H₁₉F₃N₆O, 428.2; m/z found 429 [M+H]⁺. ¹H NMR (DMSO-D₆): 8.27 (d, J=5.3 Hz, 0.3H), 8.12-7.99 (m, 2.7H), 7.85 (d, J=7.9 Hz, 0.3H), 7.72-7.54 (m, 1.6H), 7.50-7.33 (m, 1.4H), 7.13-6.92 (m, 2H), 6.82 (d, J=12.6 Hz, 0.3H), 6.78 (s, 0.7H), 6.67 (d, J=5.3 Hz, 0.7H), 4.56 (t, J=4.5 Hz, 0.7H), 4.41 (d, J=4.6 Hz, 0.3H), 4.04-3.93 (m, 0.3H), 3.86-3.72 (m, 1H), 3.52 (br s, 0.7H), 1.96 (dd, J=12.6, 8.0 Hz, 1H), 1.78-1.17 (m, 5H).

Example 211: (±)-(2-(2H-1,2,3-triazol-2-yl)phenyl)(2-((5-chloropyridin-2-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 209 substituting 2-chloro-6-(trifluoromethyl)pyridine with 5-chloro-2-iodopyridine. MS (ESI) mass calcd. for C₂₀H₁₉ClN₆O, 394.1; m/z found 395 [M+H]⁺. MP=157.0° C. ¹H NMR (DMSO-D₆): 8.14-7.99 (m, 2.3H), 7.87-7.79 (m, 1H), 7.71-7.52 (m, 1.7H), 7.52-7.36 (m, 2.6H), 7.23-7.11 (m, 0.7H), 6.80 (d, J=6.4 Hz, 0.7H), 6.58 (d, J=9.0 Hz, 0.3H), 6.52 (d, J=8.9 Hz, 0.7H), 4.53 (t, J=4.6 Hz, 0.7H), 4.37 (d, J=4.6 Hz, 0.3H), 3.92-3.82 (m, 0.3H), 3.81-3.68 (m, 1H), 3.52 (d, J=4.3 Hz, 0.7H), 1.94 (dd, J=12.5, 8.1 Hz, 1H), 1.73-1.22 (m, 5H).

Example 212: (±)-(2-(2H-1,2,3-triazol-2-yl)phenyl)(2-((6-(trifluoromethyl)pyridazin-3-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 209 substituting 2-chloro-6-(trifluoromethyl)pyridine with 3-chloro-6-(trifluoromethyl)pyridazine. MP=134.0° C. MS (ESI) mass calcd. for C₂₀H₁₈F₃N₇O, 429.2; m/z found 430 [M+H]⁺. ¹H NMR (DMSO-D₆): 8.08 (s, 1.4H), 8.07 (s, 0.6H), 7.85 (d, J=7.8 Hz, 0.3H), 7.77-7.46 (m, 3.6H), 7.44-7.31 (m, 1.4H), 7.20-7.09 (m, 0.7H), 7.06 (d, J=9.4 Hz, 0.3H), 6.98 (d, J=9.3 Hz, 0.7H), 4.59 (t, J=4.4 Hz, 0.7H), 4.48 (d, J=4.7 Hz, 0.3H), 3.97-3.87 (m, 0.7H), 3.81 (t, J=4.0 Hz, 0.3H), 3.58-3.56 (m, 1H), 2.01 (dd, J=12.9, 8.0 Hz, 1H), 1.82-1.18 (m, 5H).

Example 213: (±)-(2-(2H-1,2,3-triazol-2-yl)phenyl)(2-((5-methoxypyridin-2-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 209 substituting 2-chloro-6-(trifluoromethyl)pyridine with 2-chloro-5-methoxypyridine. MS (ESI) mass calcd. for C₂₁H₂₂N₆O₂, 390.2; m/z found 391 [M+H]⁺. MP=174.0° C. ¹H NMR (DMSO-D₆): 8.31 (s, 0.3H), 8.13-8.02 (m, 2H), 7.84 (d, J=8.0 Hz, 0.3H), 7.79 (d, J=3.0 Hz, 0.3H), 7.71-7.61 (m, 1.3H), 7.60-7.53 (m, 1H), 7.50-7.37 (m, 1.4H), 7.22-7.04 (m, 1.7H), 6.52 (d, J=9.0 Hz, 0.3H), 6.46 (d, J=9.0 Hz, 0.7H), 6.21 (d, J=6.9 Hz, 0.7H), 4.52 (t, J=4.5 Hz, 0.7H), 4.37 (d, J=4.5 Hz, 0.2H), 3.90-3.79 (m, 0.3H), 3.79-3.68 (m, 1.9H), 3.64 (s, 2.1H), 3.57 (d, J=4.0 Hz, 0.7H), 1.98-1.84 (m, 1H), 1.76-1.21 (m, 5H).

Example 214: (±)-(2-(2H-1,2,3-triazol-2-yl)phenyl)(2-((5-methylpyridin-2-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 209 substituting 2-chloro-6-(trifluoromethyl)pyridine with 2-chloro-5-methylpyridine. MS (ESI) mass calcd. for C₂₁H₂₂N₆O, 374.2; m/z found 375.2 [M+H]⁺. ¹H NMR (DMSO-D₆): 8.32 (s, 0.7H), 8.09 (s, 0.6H), 8.07 (s, 1.4H), 7.89-7.80 (m, 0.6H), 7.72-7.53 (m, 2.1H), 7.52-7.37 (m, 1.3H), 7.27 (dd, J=8.5, 2.2 Hz, 0.3H), 7.23-7.11 (m, 1.3H), 6.47 (d, J=8.5 Hz, 0.3H), 6.41 (d, J=8.2 Hz, 0.7H), 6.35 (d, J=6.9 Hz, 0.7H), 4.53 (t, J=4.5 Hz, 0.7H), 4.37 (d, J=4.4 Hz, 0.3H), 3.95-3.84 (m, 0.3H), 3.84-3.70 (m, 1H), 3.56 (d, J=4.3 Hz, 0.7H), 2.12 (s, 0.9H), 2.04 (s, 2.1H), 1.99-1.86 (m, 1H), 1.78-1.24 (m, 5H).

Example 215: (±)-(2-(2H-1,2,3-triazol-2-yl)phenyl)(2-(pyridin-2-ylamino)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 209 substituting 2-chloro-6-(trifluoromethyl)pyridine with 2-iodopyridine. MS (ESI) mass calcd. for C₂₀H₂₀N₆O, 360.2; m/z found 361 [M+H]⁺. MP=167.9° C. ¹H NMR (DMSO-D₆): 8.12-8.00 (m, 2.3H), 7.88-7.79 (m, 1H), 7.73-7.53 (m, 1.5H), 7.50-7.28 (m, 2.5H), 7.13 (t, J=7.4 Hz, 0.7H), 6.63-6.37 (m, 3H), 4.54 (t, J=4.5 Hz, 0.7H), 4.39 (d, J=4.4 Hz, 0.3H), 3.92 (td, J=7.5, 3.2 Hz, 0.3H), 3.86-3.73 (m, 1H), 3.58 (d, J=4.3 Hz, 0.7H), 2.02-1.86 (m, 1H), 1.78-1.23 (m, 5H).

Example 216: (±)-(2-(2H-1,2,3-triazol-2-yl)phenyl)(2-((5-chlorobenzo[d]oxazol-2-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Step A: (±)-tert-butyl 2-((5-chlorobenzo[d]oxazol-2-yl)amino)-7-azabicyclo[2.2.1]heptane-7-carboxylate. To intermediate B-6 (116 mg, 0.6 mmol) in 1,4-dioxane (3 mL) was added DIPEA (190 μL, 1.1 mmol) and 5-chloro-2-(methylsulfinyl)benzo[d]oxazole (235 mg, 1.1 mmol). After heating at 80° C. for 4 h, the mixture was cooled to rt and saturated NaHCO₃ (aq) was added. The aqueous layer was extracted with EtOAc (3×). The combined organics were dried (MgSO₄). Purification via silica gel chromatography (0-10% EtOAc in hexanes) gave the title compound (130 mg, 66%). MS (ESI) mass calcd. for C₁₈H₂₂ClN₃O₃, 363.1; m/z found 364.0 [M+H]⁺.

Step B: N-((±)-7-azabicyclo[2.2.1]heptan-2-yl)-5-chlorobenzo[d]oxazol-2-amine hydrochloride. Prepared analogous to Example 209 substituting (±)-tert-butyl-2-((6-(trifluoromethyl)pyridin-2-yl)amino)-7-azabicyclo[2.2.1]heptane-7-carboxylate with the title compound of step A. MS (ESI) mass calcd. for C₁₃H₁₄ClN₃O, 263.1; m/z found 264.0 [M+H]⁺.

Step C: (±)-(2-(2H-1,2,3-triazol-2-yl)phenyl)(2-((5-chlorobenzo[d]oxazol-2-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)methanone. Prepared analogous to Example 209 substituting (±)-N-(6-(trifluoromethyl)pyridin-2-yl)-7-azabicyclo[2.2.1]heptan-2-amine hydrochloride with the title compound of step B. MS (ESI) mass calcd. for C₂₂H₁₉ClN₆O₂, 434.1; m/z found 435 [M+H]⁺. ¹H NMR (DMSO-D₆): 8.20 (d, J=5.6 Hz, 1H), 8.13-8.05 (m, 2H), 7.85 (d, J=7.4 Hz, 0.3H), 7.76 (d, J=7.3 Hz, 0.3H), 7.72-7.55 (m, 1.3H), 7.53-7.44 (m, 0.7H), 7.44-7.29 (m, 2H), 7.24 (d, J=2.1 Hz, 0.7H), 7.16-7.08 (m, 0.7H), 7.08-6.98 (m, 1H), 4.66-4.47 (m, 1H), 3.97-3.86 (m, 0.3H), 3.82 (t, J=3.9 Hz, 0.3H), 3.79-3.66 (m, 1.4H), 2.07-1.92 (m, 1H), 1.88-1.22 (m, 5H).

Example 217: (±)-(2-((5-bromopyridin-2-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)(6-methyl-3-(pyrimidin-2-yl)pyridin-2-yl)methanone

Prepared analogous to Example 209 substituting 2-chloro-6-(trifluoromethyl)pyridine with 5-bromo-2-iodopyridine and intermediate A-1 with intermediate A-9. MS (ESI) mass calcd. for C₂₂H₂₁BrN₆O, 464.1; m/z found 466 [M+H]⁺. MP=221.8° C. ¹H NMR (DMSO-D₆): 8.96-8.78 (m, 2H), 8.32 (d, J=8.0 Hz, 0.3H), 8.19 (d, J=8.0 Hz, 0.7H), 8.10 (d, J=2.4 Hz, 0.3H), 7.93 (d, J=2.4 Hz, 0.7H), 7.56 (dd, J=8.9, 2.5 Hz, 0.3H), 7.51-7.39 (m, 2H), 7.33 (d, J=8.1 Hz, 0.7H), 6.93 (d, J=7.1 Hz, 0.7H), 6.66 (d, J=5.6 Hz, 0.3H), 6.61 (d, J=9.0 Hz, 0.3H), 6.36 (d, J=8.9 Hz, 0.7H), 4.59 (t, J=4.1 Hz, 0.7H), 4.47 (d, J=4.3 Hz, 0.3H), 3.96-3.75 (m, 2H), 2.58 (s, 0.9H), 2.31 (s, 2.1H), 2.07-1.91 (m, 1H), 1.88-1.30 (m, 5H).

Example 218: (±)-(2-((5-bromopyridin-2-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)(3-fluoro-2-methoxyphenyl)methanone

Prepared analogous to Example 217 substituting intermediate A-9 with 3-fluoro-2-methoxybenzoic acid. MS (ESI) mass calcd. for C₁₉H₁₉BrFN₃O₂, 419.1; m/z found 420.1 [M+H]⁺. MP=175.2° C. ¹H NMR (DMSO-D₆): 8.10 (d, J=2.4 Hz, 0.3H), 7.90 (d, J=2.4 Hz, 0.7H), 7.56 (dd, J=8.9, 2.5 Hz, 0.3H), 7.47 (dd, J=8.9, 2.5 Hz, 0.7H), 7.34 (ddd, J=11.7, 7.5, 2.3 Hz, 0.3H), 7.24-7.08 (m, 1.3H), 7.02 (d, J=7.6 Hz, 0.7H), 6.87-6.66 (m, 1.7H), 6.54 (d, J=8.9 Hz, 0.3H), 6.46 (d, J=8.9 Hz, 0.7H), 4.63 (br s, 0.7H), 4.50 (d, J=4.8 Hz, 0.3H), 3.88-3.68 (m, 4.3H), 3.58 (d, J=2.9 Hz, 0.7H), 2.05-1.87 (m, 1H), 1.78-1.20 (m, 5H).

Example 219: (±)-(2-((5-bromopyridin-2-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)(3-ethoxy-6-methylpyridin-2-yl)methanone

Prepared analogous to Example 217 substituting intermediate A-9 with intermediate A-8. MS (ESI) mass calcd. for C₂₀H₂₃BrN₄O₂, 430.1; m/z found 431.1 [M+H]⁺. MP=134.5° C. ¹H NMR (DMSO-D₆): 8.10 (d, J=2.4 Hz, 0.3H), 7.88 (d, J=2.4 Hz, 0.7H), 7.55 (dd, J=8.9, 2.5 Hz, 0.3H), 7.50-7.41 (m, 1H), 7.30 (d, J=8.6 Hz, 0.7H), 7.24 (d, J=8.6 Hz, 0.3H), 7.08 (d, J=8.6 Hz, 0.7H), 6.76 (d, J=5.7 Hz, 0.7H), 6.63 (d, J=5.3 Hz, 0.3H), 6.57 (d, J=8.9 Hz, 0.3H), 6.43 (d, J=8.9 Hz, 0.7H), 4.62 (br s, 0.7H), 4.51 (d, J=2.8 Hz, 0.3H), 4.13-3.88 (m, 2H), 3.83-3.73 (m, 0.3H), 3.72-3.61 (m, 1H), 3.59 (d, J=3.5 Hz, 0.7H), 2.39 (s, 0.9H), 2.21 (s, 2.1H), 2.02-1.85 (m, 1H), 1.75-1.33 (m, 5H), 1.25 (td, J=6.9, 3.6 Hz, 3H).

Example 220: (±)-(2-((5-bromopyridin-2-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)(6-methyl-3-(2H-1,2,3-triazol-2-yl)pyridin-2-yl)methanone

Prepared analogous to Example 217 substituting intermediate A-9 with intermediate A-21. MS (ESI) mass calcd. for C₂₀H₂₀BrN₇O, 453.1; m/z found 454.1 [M+H]⁺. MP=214.9° C. ¹H NMR (DMSO-D₆): 8.18 (d, J=8.4 Hz, 0.3H), 8.14-8.09 (m, 2.3H), 8.05 (d, J=8.4 Hz, 0.7H), 7.93 (d, J=2.4 Hz, 0.7H), 7.62-7.53 (m, 0.6H), 7.50 (dd, J=8.9, 2.5 Hz, 0.7H), 7.40 (d, J=8.4 Hz, 0.7H), 6.76 (d, J=6.3 Hz, 0.7H), 6.61 (d, J=8.9 Hz, 0.3H), 6.52 (d, J=5.7 Hz, 0.3H), 6.45 (d, J=8.9 Hz, 0.7H), 4.58 (t, J=4.5 Hz, 0.7H), 4.47 (d, J=4.8 Hz, 0.3H), 3.91 (t, J=4.3 Hz, 0.3H), 3.88-3.68 (m, 1.7H), 2.60 (s, 0.9H), 2.31 (s, 2.1H), 2.03-1.90 (m, 1H), 1.81-1.29 (m, 5H).

Example 221: (±)-(2-(2H-1,2,3-triazol-2-yl)phenyl)(2-((5-(trifluoromethyl)pyrimidin-2-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 220 substituting intermediate A-21 with intermediate A-1. MP=167.1° C. ¹H NMR (DMSO-D₆): 8.75 (s, 0.4H), 8.70 (s, 0.4H), 8.66 (s, 0.6H), 8.53 (s, 0.6H), 8.12-8.03 (m, 2.6H), 7.86 (d, J=7.3 Hz, 0.4H), 7.80 (d, J=7.2 Hz, 0.4H), 7.72-7.54 (m, 1.6H), 7.48-7.34 (m, 1.4H), 7.16 (t, J=7.4 Hz, 0.6H), 4.56 (br s, 0.6H), 4.41 (d, J=4.3 Hz, 0.4H), 4.08 (dd, J=11.1, 6.8 Hz, 0.4H), 3.90-3.75 (m, 1H), 3.61 (d, J=4.3 Hz, 0.6H), 2.01-1.27 (m, 6H).

Example 222: (±)-(3-fluoro-2-methoxyphenyl)(2-((5-(trifluoromethyl)pyrimidin-2-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 221 substituting intermediate A-1 with 3-fluoro-2-methoxybenzoic acid. ¹H NMR (DMSO-D₆): 8.72 (br d, J=22.6 Hz, 0.8H), 8.58 (br d, J=24.1 Hz, 1.2H), 8.12 (br d, J=5.6 Hz, 0.4H), 7.99 (br d, J=5.0 Hz, 0.6H), 7.45-7.23 (m, 0.8H), 7.26-7.06 (m, 1.2H), 6.97 (d, J=7.5 Hz, 0.6H), 6.90-6.72 (m, 0.6H), 4.65 (br s, 0.6H), 4.53 (d, J=4.8 Hz, 0.4H), 3.97 (dd, J=11.4, 6.0 Hz, 0.4H), 3.84 (s, 1.2H), 3.93-3.71 (m, 1H), 3.78 (s, 1.8H), 3.69 (br d, J=2.9 Hz, 0.6H), 2.06-1.35 (m, 6H)

Example 223: (±)-(6-methyl-3-(2H-1,2,3-triazol-2-yl)pyridin-2-yl)(2-((5-(trifluoromethyl)pyrimidin-2-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 221 substituting intermediate A-1 with intermediate A-21. ¹H NMR (DMSO-D₆): 8.74 (br d, J=12.1 Hz, 0.4H), 8.63 (br d, J=13.2 Hz, 1.2H), 8.26-8.01 (m, 3.4H), 7.61 (dd, J=21.8, 7.4 Hz, 0.4H), 7.43 (d, J=8.4 Hz, 0.6H), 4.61 (br s, 0.6H), 4.55 (d, J=5.0 Hz, 0.4H), 4.11-4.01 (m, 0.4H), 4.02-3.93 (m, 1H), 3.88 (dd, J=10.1, 6.1 Hz, 0.6H), 3.22-3.06 (m, 1H), 2.60 (s, 1H), 2.30 (s, 2H), 2.06-1.34 (n, 6H).

Example 224: (±)-(3-ethoxy-6-methylpyridin-2-yl)(2-((5-(trifluoromethyl)pyrimidin-2-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 221 substituting intermediate A-1 with intermediate A-8. ¹H NMR (DMSO-D₆): 8.79 (br d, J=22.9 Hz, 0.6H), 8.65 (br d, J=17.4 Hz, 1.4H), 8.21 (d, J=5.3 Hz, 0.7H), 7.92 (d, J=5.2 Hz, 0.3H), 7.52 (d, J=8.6 Hz, 0.3H), 7.42 (d, J=8.6 Hz, 0.7H), 7.32 (d, J=8.6 Hz, 0.3H), 7.18 (d, J=8.6 Hz, 0.7H), 4.71 (br s, 0.7H), 4.64 (br d, J=4.7 Hz, 0.3H), 4.23-3.93 (m, 2.5H), 3.93-3.78 (m, 1.4H), 3.78-3.55 (m, 1.7H), 3.31-3.07 (m, 1.4H), 2.47 (s, 1H), 2.31 (s, 2H), 2.06-1.40 (m, 6H).

Example 225: (±)-(6-methyl-3-(pyrimidin-2-yl)pyridin-2-yl)(2-((5-(trifluoromethyl)pyrimidin-2-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 221 substituting intermediate A-1 with intermediate A-9. MP=203° C. MS (ESI) mass calcd. for C₂₂H₂₀F₃N₇O, 455.2; m/z found 427.5 [M+H]⁺. ¹H NMR (DMSO-D₆): 8.94 (d, J=4.9 Hz, 0.4H), 8.89 (d, J=4.9 Hz, 1.6H), 8.77 (s, 0.2H), 8.71 (s, 0.2H), 8.61 (s, 1.4H), 8.36 (d, J=8.1 Hz, 0.2H), 8.24 (d, J=7.9 Hz, 1.8H), 7.72 (d, J=6.0 Hz, 0.2H), 7.54-7.44 (m, 1.2H), 7.38 (d, J=8.1 Hz, 0.8H), 4.64 (br s, 0.8H), 4.58 (d, J=4.6 Hz, 0.2H), 4.06-3.90 (m, 2H), 2.60 (s, 0.6H), 2.35 (s, 2.4H), 2.11-1.73 (m, 4H), 1.62-1.35 (m, 2H).

Example 226: (±)-(3-fluoro-2-methoxyphenyl)(2-((5-(trifluoromethyl)pyrimidin-2-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepare analogous to Example 222 substituting intermediate B-6 with intermediate B-7. MS (ESI) mass calcd. for C₁₉H₁₈F₄N₄O₂, 410.2; m/z found 411.3 [M+H]⁺. ¹H NMR (DMSO-D₆): 8.75 (s, 0.5H), 8.68 (s, 0.5H), 8.61 (s, 0.5H), 8.57 (s, 0.5H), 8.52 (d, J=6.3 Hz, 0.5H), 8.44 (d, J=6.3 Hz, 0.5H), 7.44-7.29 (m, 1H), 7.23-7.08 (m, 2H), 4.82 (t, J=3.9 Hz, 0.5H), 4.58 (t, J=4.5 Hz, 0.5H), 4.34-4.12 (m, 1H), 3.94-3.81 (m, 3.5H), 3.68 (t, J=4.2 Hz, 0.5H), 2.31-2.11 (m, 1H), 1.93-1.40 (m, 5H).

Example 227: (±)-(3-ethoxy-6-methylpyridin-2-yl)(2-((5-(trifluoromethyl)pyrimidin-2-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepare analogous to Example 224 substituting intermediate B-6 with intermediate B-7. MP=79.7° C. MS (ESI) mass calcd. for C₂₀H₂₂F₃N₅O₂, 421.2; m/z found 422.4 [M+H]⁺. ¹H NMR (DMSO-D₆): 8.76 (s, 0.5H), 8.68 (s, 0.5H), 8.61 (s, 0.5H), 8.56 (s, 0.5H), 8.52 (d, J=6.4 Hz, 0.5H), 8.44 (d, J=6.6 Hz, 0.5H), 7.48 (d, J=3.2 Hz, 0.5H), 7.45 (d, J=3.2 Hz, 0.5H), 7.28 (d, J=3.3 Hz, 0.5H), 7.25 (d, J=3.3 Hz, 0.5H), 4.83 (t, J=4.2 Hz, 0.5H), 4.59 (t, J=4.3 Hz, 0.5H), 4.40-4.29 (m, 0.5H), 4.28-4.19 (m, 0.5H), 4.16-4.01 (m, 2H), 3.79 (t, J=4.4 Hz, 0.5H), 3.61 (t, J=4.6 Hz, 0.5H), 2.41 (s, 1.5H), 2.40 (s, 1.5H), 2.30-2.09 (m, 1H), 1.93-1.41 (m, 5H), 1.34-1.23 (m, 3H).

Example 228: (±)-(6-methyl-3-(2H-1,2,3-triazol-2-yl)pyridin-2-yl)(2-((5-(trifluoromethyl)pyrimidin-2-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepare analogous to Example 223 substituting intermediate B-6 with intermediate B-7. MS (ESI) mass calcd. for C₂₀H₁₉F₃N₈O, 444.2; m/z found 445.4 [M+H]⁺. MP=89.1° C. ¹H NMR (DMSO-D₆): 8.77 (s, 0.6H), 8.68 (s, 0.6H), 8.61 (s, 0.4H), 8.55 (s, 0.4H), 8.51 (d, J=6.3 Hz, 0.6H), 8.44 (d, J=6.3 Hz, 0.4H), 8.24-8.16 (m, 1H), 8.13 (s, 1H), 8.12 (s, 1H), 7.63-7.52 (m, 1H), 4.81 (t, J=4.2 Hz, 0.6H), 4.55 (t, J=4.2 Hz, 0.4H), 4.40-4.21 (m, 1H), 4.06 (t, J=4.4 Hz, 0.4H), 3.79 (t, J=4.4 Hz, 0.6H), 2.61 (s, 1.2H), 2.58 (s, 1.8H), 2.34-2.20 (m, 0.6H), 2.19-2.03 (m, 0.6H), 1.94-1.50 (m, 4.2H), 1.44 (dd, J=12.3, 4.6 Hz, 0.6H).

Example 229: (±)-(3-ethoxy-6-methylpyridin-2-yl)(2-(quinoxalin-2-ylamino)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepare analogous to Example 207 substituting intermediate B-6 with intermediate B-7. MS (ESI) mass calcd. for C₂₃H₂₅N₅O₂, 403.2; m/z found 404.5 [M+H]⁺. MP=115.1° C. ¹H NMR (DMSO-D₆): 8.37 (s, 0.5H), 8.30 (s, 0.5H), 7.97 (t, J=5.4 Hz, 1H), 7.80 (d, J=7.4 Hz, 0.5H), 7.75 (d, J=7.1 Hz, 0.5H), 7.69-7.44 (m, 2.5H), 7.43-7.23 (m, 2.5H), 4.99 (t, J=4.4 Hz, 0.5H), 4.63 (t, J=4.6 Hz, 0.5H), 4.48-4.27 (m, 1H), 4.26-4.13 (m, 2H), 3.96 (t, J=4.4 Hz, 0.5H), 3.64 (t, J=4.6 Hz, 0.5H), 2.44 (s, 1.5H), 2.41 (s, 1.5H), 2.39-2.26 (m, 1H), 1.98-1.37 (m, 5H), 1.36-1.28 (m, 3H).

Example 230: (±)-(6-methyl-3-(2H-1,2,3-triazol-2-yl)pyridin-2-yl)(2-(quinoxalin-2-ylamino)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepare analogous to Example 205 substituting intermediate B-6 with intermediate B-7. MS (ESI) mass calcd. for C₂₃H₂₂N80, 426.2; m/z found 427.5 [M+H]⁺. MP=152.3° C. ¹H NMR (DMSO-D₆): 8.37 (s, 0.5H), 8.28-8.20 (m, 2H), 8.16-8.13 (m, 2H), 7.95 (dd, J=5.6, 3.6 Hz, 1H), 7.79 (d, J=8.1 Hz, 0.5H), 7.74 (d, J=8.1 Hz, 0.5H), 7.70-7.48 (m, 2.5H), 7.41-7.23 (m, 1.5H), 4.98 (t, J=4.2 Hz, 0.5H), 4.60 (t, J=4.6 Hz, 0.5H), 4.36-4.24 (m, 1H), 4.19 (t, J=4.5 Hz, 0.5H), 3.81 (t, J=4.6 Hz, 0.5H), 2.67 (s, 1.5H), 2.60 (s, 1.5H), 2.43-2.17 (m, 1H), 1.97-1.25 (m, 5H).

Example 231: (±)-(3-fluoro-2-methoxyphenyl)(2-(quinoxalin-2-ylamino)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepare analogous to Example 206 substituting intermediate B-6 with intermediate B-7. ¹H NMR (DMSO-D₆): 8.36 (s, 0.5H), 8.29 (s, 0.5H), 8.08-7.95 (m, 1H), 7.85-7.69 (m, 1H), 7.69-7.49 (m, 1.5H), 7.49-7.27 (m, 2H), 7.27-7.12 (m, 2.5H), 5.00 (t, J=4.2 Hz, 0.5H), 4.62 (t, J=4.2 Hz, 0.5H), 4.43-4.17 (m, 1H), 4.11 (t, J=4.3 Hz, 0.5H), 3.95 (s, 1.5H), 3.88 (s, 1.5H), 3.72 (t, J=4.5 Hz, 0.5H), 2.45-2.25 (m, 1H), 1.99-1.46 (m, 4H), 1.46-1.28 (m, 1H).

Example 232: (±)-(2-((5-bromopyridin-2-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)(6-methyl-3-(2H-1,2,3-triazol-2-yl)pyridin-2-yl)methanone

Prepare analogous to Example 220 substituting intermediate B-6 with intermediate B-7. MP=196.0° C. ¹H NMR (DMSO-D₆): 8.25-8.16 (m, 1H), 8.16-8.10 (m, 2.6H), 7.90 (d, J=2.4 Hz, 0.4H), 7.63-7.53 (m, 1.6H), 7.50 (dd, J=8.9, 2.5 Hz, 0.4H), 7.19 (d, J=6.0 Hz, 0.6H), 7.12 (d, J=6.1 Hz, 0.4H), 6.54 (d, J=8.9 Hz, 0.6H), 6.44 (d, J=8.9 Hz, 0.4H), 4.81 (t, J=4.2 Hz, 0.6H), 4.54 (t, J=4.2 Hz, 0.4H), 4.23-4.07 (m, 1H), 4.04 (t, J=4.5 Hz, 0.4H), 3.75 (t, J=4.5 Hz, 0.6H), 2.61 (s, 1.2H), 2.58 (s, 1.8H), 2.36-2.05 (m, 1H), 1.92-1.41 (m, 4H), 1.30 (dd, J=12.4, 4.4 Hz, 0.4H), 1.18 (dd, J=12.2, 4.6 Hz, 0.6H).

Example 233: (±)-(2-((5-bromopyridin-2-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)(3-ethoxy-6-methylpyridin-2-yl)methanone

Prepare analogous to Example 219 substituting intermediate B-6 with intermediate B-7. MP=176.1° C. H ¹H NMR (DMSO-D₆): 8.11 (d, J=2.4 Hz, 0.5H), 7.91 (d, J=2.4 Hz, 0.5H), 7.61-7.43 (m, 2H), 7.33-7.20 (m, 1.5H), 7.15 (d, J=6.1 Hz, 0.5H), 6.55 (d, J=8.9 Hz, 0.5H), 6.46 (d, J=8.9 Hz, 0.5H), 4.83 (t, J=4.3 Hz, 0.5H), 4.57 (t, J=4.6 Hz, 0.5H), 4.20 (d, J=5.5 Hz, 0.5H), 4.09 (dq, J=10.2, 6.9 Hz, 2.5H), 3.79 (t, J=4.3 Hz, 0.5H), 3.58 (t, J=4.6 Hz, 0.5H), 2.41 (s, 1.5H), 2.40 (s, 1.5H), 2.32-2.14 (m, 1H), 1.93-1.45 (m, 4H), 1.36-1.17 (m, 4H).

Example 234: (±)-(2-((5-bromopyridin-2-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)(3-fluoro-2-methoxyphenyl)methanone

Prepare analogous to Example 217 substituting intermediate B-6 with intermediate B-7. MP=144.5° C. ¹H NMR (DMSO-D₆): 8.11 (d, J=2.4 Hz, 0.6H), 7.91 (d, J=2.4 Hz, 0.4H), 7.56 (dd, J=8.9, 2.5 Hz, 0.6H), 7.50 (dd, J=8.9, 2.5 Hz, 0.4H), 7.43-7.30 (m, 1H), 7.27-7.05 (m, 3H), 6.54 (d, J=8.9 Hz, 0.6H), 6.46 (d, J=8.9 Hz, 0.4H), 4.83 (t, J=4.3 Hz, 0.6H), 4.57 (t, J=4.7 Hz, 0.4H), 4.21-3.99 (m, 1H), 3.95-3.81 (m, 3.4H), 3.66 (t, J=4.7 Hz, 0.6H), 2.36-2.14 (m, 1H), 1.94-1.43 (m, 4H), 1.36-1.14 (m, 1H).

Example 235: (±)-((2-(2H-1,2,3-triazol-2-yl)phenyl)(2-((4-(trifluoromethyl)pyridin-2-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepare analogous to Example 210 substituting intermediate B-6 with intermediate B-7. MS (ESI) mass calcd. for C₂₁H₁₉F₃N₆O, 428.2; m/z found 429 [M+H]⁺. MP=274.2° C. ¹H NMR (DMSO-D₆): 8.27 (d, J=5.2 Hz, 0.5H), 8.13-8.01 (m, 2.5H), 7.89-7.80 (m, 1H), 7.73-7.61 (m, 1H), 7.61-7.51 (m, 2H), 7.44 (d, J=6.1 Hz, 0.5H), 7.38 (d, J=5.9 Hz, 0.5H), 6.83-6.75 (m, 1H), 6.73-6.63 (m, 1H), 4.78 (t, J=3.9 Hz, 0.5H), 4.50 (t, J=4.6 Hz, 0.5H), 4.27-4.04 (m, 1H), 3.96 (t, J=4.1 Hz, 0.5H), 3.64 (t, J=4.1 Hz, 0.5H), 2.40-2.21 (m, 0.5H), 2.17-1.99 (m, 0.5H), 1.88-1.32 (m, 4H), 1.27 (dd, J=12.3, 4.3 Hz, 0.5H), 1.12 (dd, J=12.2, 4.5 Hz, 0.5H).

Example 236: (±)-(2-((5-fluoropyridin-2-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)(6-methyl-3-(2H-1,2,3-triazol-2-yl)pyridin-2-yl)methanone

Prepared analogous to Example 209 substituting 2-chloro-6-(trifluoromethyl)pyridine with 5-fluoro-2-iodopyridine and intermediate A-1 with A-21. MP=100.1° C. MS (ESI) mass calcd. for C₂₀H₂₀FN₇O, 393.2; m/z found 394.2 [M+H]⁺. ¹H NMR (DMSO-D₆): 8.24-8.15 (m, 1H), 8.12 (s, 1.2H) 8.11 (s, 0.8H), 8.00 (d, J=2.9 Hz, 0.6H), 7.80 (d, J=2.8 Hz, 0.4H), 7.63-7.51 (m, 1H), 7.43-7.26 (m, 1H), 6.94 (d, J=5.9 Hz, 0.6H), 6.87 (d, J=6.0 Hz, 0.4H), 6.55 (dd, J=9.1, 3.6 Hz, 0.6H), 6.45 (dd, J=9.1, 3.7 Hz, 0.4H), 4.81 (t, J=4.2 Hz, 0.6H), 4.52 (t, J=4.6 Hz, 0.4H), 4.19-3.99 (m, 1.4H), 3.73 (t, J=4.6 Hz, 0.6H), 2.60 (s, 1.2H), 2.58 (s, 1.8H), 2.35-2.20 (m, 0.6H), 2.19-2.05 (m, 0.4H), 1.96-1.38 (m, 4H), 1.27 (dd, J=12.5, 4.2 Hz, 0.6H), 1.15 (dd, J=12.2, 4.8 Hz, 0.4H).

Example 237: (±)-(3-fluoro-2-methoxyphenyl)(2-((5-fluoropyridin-2-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 209 substituting 2-chloro-6-(trifluoromethyl)pyridine with 5-fluoro-2-iodopyridine and intermediate A-1 with 3-fluoro-2-methoxybenzoic acid. MS (ESI) mass calcd. for C₁₉H₁₉F₂N₃O₂, 359.1; m/z found 360.2 [M+H]⁺. MP=134.7° C. ¹H NMR (DMSO-D₆): 8.00 (d, J=2.9 Hz, 0.5H), 7.80 (d, J=2.9 Hz, 0.5H), 7.45-7.26 (m, 2H), 7.24-7.06 (m, 2H), 6.96 (d, J=6.0 Hz, 0.5H), 6.89 (d, J=5.8 Hz, 0.5H), 6.56 (dd, J=9.1, 3.6 Hz, 0.5H), 6.48 (dd, J=9.2, 3.6 Hz, 0.5H), 4.83 (t, J=4.3 Hz, 0.5H), 4.56 (t, J=4.7 Hz, 0.5H), 4.18-3.98 (m, 1H), 3.95-3.81 (m, 3.5H), 3.64 (t, J=4.6 Hz, 0.5H), 2.35-2.14 (m, 1H), 1.96-1.43 (m, 4H), 1.30-1.13 (m, 1H).

Example 238: (3-fluoro-2-(pyrimidin-2-yl)phenyl)((1S,2R,4R)-2-((5-(trifluoromethyl)pyrazin-2-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Step A: (1S,2R,4R)—N-(5-(trifluoromethyl)pyrazin-2-yl)-7-azabicyclo[2.2.1]heptan-2-amine hydrochloride. To the intermediate of Example 181 Step A (100 mg, 0.3 mmol) in DCM (3 mL) was added 4M HCl in dioxane (0.8 mL). The reaction was allowed to proceed overnight then concentrated neutralized with 5% Na₂CO₃ (aq) and extracted with DCM (2×). The combined organics were dried (Na₂SO₄) to give the title compound of step A that was used without further purification.

Step B: (3-fluoro-2-(pyrimidin-2-yl)phenyl)((1S,2R,4R)-2-((5-(trifluoromethyl)pyrazin-2-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)methanone. To the title compound of step A (1.44 g, 5.6 mmol) in DCM (56 mL) was added DIPEA (1.25 mL, 7.3 mmol) and intermediate A-2 (1.43 g, 6.1 mmol). Then T3P (50% solution in DMF, 10 mL, 17 mmol) was added dropwise and the reaction heated at 45° C. for 16 h. After allowing to cool to rt, DCM was added and the mixture washed with H₂O then saturated NaHCO₃ (aq). The combined aq layers were extracted with DCM. The combined organic layers were dried (Na₂SO₄). Purification via silica gel chromatography (10-100% EtOAc in hexanes) gave the title compound (2 g, 78%). MS (ESI) mass calcd. for C₂₂H₁₈F₄N₆O, 458.2; m/z found 459.1 [M+H]⁺. ¹H NMR (CDCl₃) 8.91-8.73 (m, 2H), 8.35-8.22 (m, 1H), 8.19 (s, 1H), 7.66 (s, 1H), 7.44-7.13 (m, 4H), 4.79-4.68 (m, 1H), 4.46-4.35 (m, 1H), 4.12-4.03 (m, 1H), 2.22-2.00 (m, 2H), 1.99-1.84 (m, 1H), 1.79-1.45 (m, 3H).

Example 239: (2-ethoxynaphthalen-1-yl)((1S,2R,4R)-2-((5-(trifluoromethyl)pyrazin-2-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 181 substituting intermediate A-1 with 2-ethoxy-1-naphthoic acid. MS (ESI) mass calcd. for C₂₄H₂₃F₃N₄O₂, 456.2; m/z found 457.2 [M+H]⁺. ¹H NMR (CDCl₃): 8.39-8.31 (m, 0.3H), 8.18 (s, 0.5H), 8.08-7.98 (m, 0.3H), 7.96-7.67 (m, 3.6H), 7.57-7.32 (m, 2H), 7.31-7.16 (m, 1.3H), 7.10-7.04 (m, 0.2H), 6.34 (d, J=9.1 Hz, 0.5H), 5.90-5.75 (m, 0.3H), 5.17-4.95 (m, 1H), 4.70 (d, J=7.1 Hz, 0.2H), 4.49-4.07 (m, 2.7H), 3.90 (td, J=7.4, 2.9 Hz, 0.2H), 3.77-3.65 (m, 0.3H), 3.62-3.56 (m, 0.2H), 3.39 (d, J=5.1 Hz, 0.4H), 2.30-1.94 (m, 2H), 1.81-1.47 (m, 5H), 1.47-1.33 (m, 2H).

Example 240: isoquinolin-4-yl((1S,2R,4R)-2-((5-(trifluoromethyl)pyrazin-2-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 181 substituting intermediate A-1 with isoquinoline-4-carboxylic acid. MS (ESI) mass calcd. for C₂₁H₁₈F₃N₅O, 413.2; m/z found 414.2 [M+H]⁺. ¹H NMR (CDCl₃): 9.31 (s, 0.5H), 9.13 (s, 0.5H), 8.68-8.49 (m, 1H), 8.40-7.53 (m, 5.5H), 7.42 (s, 0.5H), 6.20 (s, 0.5H), 4.99 (s, 1.5H), 4.21 (s, 0.5H), 4.06-3.77 (m, 1.5H), 2.27-1.43 (m, 6H).

Example 241: (4-methoxy-2-(2H-1,2,3-triazol-2-yl)phenyl)((1S,2R,4R)-2-((5-(trifluoromethyl)pyrazin-2-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 181 substituting intermediate A-1 with intermediate A-5. MS (ESI) mass calcd. for C₂₁H₂₀F₃N₇O₂, 459.2; m/z found 460.3 [M+H]⁺. ¹H NMR (CDCl₃): 8.31 (s, 0.3H), 8.18 (s, 0.7H), 7.91 (s, 1.5H), 7.87-7.77 (m, 1H), 7.54 (s, 0.8H), 7.48-7.39 (m, 0.7H), 7.35-7.28 (m, 1.7H), 6.97 (dd, J=8.5, 2.5 Hz, 0.3H), 6.87 (d, J=8.3 Hz, 0.7H), 6.29 (s, 0.3H), 4.85-4.79 (m, 0.7H), 4.75-4.70 (m, 0.3H), 4.40-4.22 (m, 1H), 4.09-4.03 (m, 0.3H), 3.99 (s, 0.7H), 3.94-3.83 (m, 3H), 2.19-1.41 (m, 6H).

Example 242: (2-methoxy-6-(2H-1,2,3-triazol-2-yl)phenyl)((1S,2R,4R)-2-((5-(trifluoromethyl)pyrazin-2-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 181 substituting intermediate A-1 with intermediate A-13. MS (ESI) mass calcd. for C₂₁H₂₀F₃N₇O₂, 459.2; m/z found 460.3 [M+H]⁺. ¹H NMR (CDCl₃): 8.37-8.30 (m, 0.3H), 8.25-8.17 (m, 0.7H), 7.97-7.85 (m, 1.5H), 7.84-7.74 (m, 0.8H), 7.65-7.56 (m, 0.4H), 7.55-7.37 (m, 2.7H), 7.05-6.94 (m, 1H), 6.17-5.98 (m, 0.2H), 5.90-5.66 (m, 0.4H), 5.02-4.86 (m, 0.7H), 4.86-4.71 (m, 0.3H), 4.45-4.18 (m, 0.8H), 4.05 (s, 0.7H), 3.97-3.75 (m, 3.3H), 3.62-3.57 (m, 0.2H), 2.25-1.29 (m, 6H).

Example 243: (5-fluoro-2-(pyrimidin-2-yl)phenyl)((1S,2R,4R)-2-((5-(trifluoromethyl)pyrazin-2-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 181 substituting intermediate A-1 with intermediate A-7. MS (ESI) mass calcd. for C₂₂H₁₈F₄N₆O, 458.2; m/z found 459.3 [M+H]⁺. ¹H NMR (CDCl₃): 8.88-8.79 (m, 1.7H), 8.77-8.69 (m, 0.3H), 8.36-8.14 (m, 1.8H), 8.01 (dd, J=8.6, 5.4 Hz, 1H), 7.81 (s, 0.2H), 7.42-7.30-7.02 (m, 3.8H), 6.26 (d, J=7.8 Hz, 0.2H), 4.90-4.81 (m, 0.8H), 4.74 (d, J=5.2 Hz, 0.2H), 4.42 (s, 0.8H), 4.27 (s, 0.2H), 4.12-3.96 (m, 1H), 2.29-1.39 (m, 6H).

Example 244: (5-(4-fluorophenyl)-2-methylthiazol-4-yl)((1S,2R,4R)-2-((5-(trifluoromethyl)pyrazin-2-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 181 substituting intermediate A-1 with 5-(4-fluorophenyl)-2-methylthiazole-4-carboxylic acid. MS (ESI) mass calcd. for C₂₂H₁₉F₄N₅OS, 477.2; m/z found 478.1 [M+H]⁺. ¹H NMR (CDCl₃): 8.32-8.20 (m, 1H), 7.95-7.84 (m, 1H), 7.56-7.40 (m, 2H), 7.15-7.04 (m, 2H), 6.97-6.77 (m, 0.8H), 6.01-5.88 (m, 0.2H), 4.85 (t, J=4.5 Hz, 1H), 4.21-3.90 (m, 2H), 2.80-2.56 (m, 3H), 2.19-1.95 (m, 1.7H), 1.93-1.31 (m, 4.3H).

Example 245: (3-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl)((1S,2R,4R)-2-((5-(trifluoromethyl)pyrazin-2-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 181 substituting intermediate A-1 with intermediate A-24. MS (ESI) mass calcd. for C₂₁H₂₀F₃N₇O, 443.2; m/z found 444.3 [M+H]⁺. ¹H NMR (CDCl₃): 8.29-8.23 (m, 0.2H), 8.21-8.15 (m, 0.8H), 7.95-7.88 (m, 1.6H), 7.84-7.74 (m, 1.3H), 7.62-7.39 (m, 1.2H), 7.37-7.19 (m, 2.7H), 5.81 (s, 0.2H), 4.79-4.65 (m, 0.8H), 4.61-4.51 (m, 0.2H), 4.38-3.90 (m, 2H), 2.19 (s, 3H), 2.14-1.42 (m, 6H).

Example 246: (3-ethoxyisoquinolin-4-yl)((1S,2R,4R)-2-((5-(trifluoromethyl)pyrazin-2-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 181 substituting intermediate A-1 with intermediate A-22. MS (ESI) mass calcd. for C₂₃H₂₂F₃N₅O₂, 457.2; m/z found 458.3 [M+H]⁺. ¹H NMR (CDCl₃): 9.01-8.92 (m, 0.8H), 8.82 (s, 0.2H), 8.35 (s, 0.5H), 8.22 (s, 0.3H), 8.05 (s, 0.1H), 8.00-7.85 (m, 1.6H), 7.84-7.71 (m, 1H), 7.71-7.54 (m, 1.2H), 7.50-7.39 (m, 0.8H), 7.39-7.31 (m, 0.4H), 7.18 (s, 0.3H), 6.11 (s, 0.1H), 5.95 (d, J=8.8 Hz, 0.3H), 5.83 (d, J=8.0 Hz, 0.4H), 5.15-5.06 (m, 0.3H), 5.06-4.94 (m, 0.7H), 4.92-4.72 (m, 0.5H), 4.68-4.41 (m, 1.5H), 4.40-4.30 (m, 0.3H), 4.24-4.07 (m, 0.4H), 3.89-3.81 (m, 0.2H), 3.81-3.67 (m, 0.7H), 3.51 (d, J=5.1 Hz, 0.3H), 2.30-1.95 (m, 2.5H), 1.91-1.21 (m, 6.5H).

Example 247: (6-methyl-2-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)((1S,2R,4R)-2-((5-(trifluoromethyl)pyrazin-2-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 181 substituting intermediate A-1 with intermediate A-3. MS (ESI) mass calcd. for C₂₀H₁₉F₃N₈O, 444.2; m/z found 445.2 [M+H]⁺. ¹H NMR (CDCl₃): 8.32 (s, 0.4H), 8.18 (s, 0.6H), 7.96 (s, 1.3H), 7.88 (d, J=4.6 Hz, 1.1H), 7.79 (d, J=7.7 Hz, 0.5H), 7.73-7.52 (m, 1.5H), 7.35-7.27 (m, 0.5H), 7.18 (s, 0.7H), 6.28 (s, 0.4H), 4.89-4.70 (m, 1H), 4.42-4.19 (m, 1H), 4.03-3.81 (m, 1H), 2.76-2.56 (m, 3H), 2.26-1.40 (m, 6H).

Example 248: (6-methyl-2-(1H-1,2,3-triazol-1-yl)pyridin-3-yl)((1S,2R,4R)-2-((5-(trifluoromethyl)pyrazin-2-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 181 substituting intermediate A-1 with intermediate A-4. MS (ESI) mass calcd. for C₂₀H₁₉F₃N₈O, 444.2; m/z found 445.2 [M+H]⁺. ¹H NMR (CDCl₃): 8.51-8.35 (m, 1.6H), 8.29 (s, 0.7H), 8.17 (s, 0.3H), 7.92-7.80 (m, 1H), 7.76-7.60 (m, 1.3H), 7.35-7.18 (m, 1.4H), 6.81-6.61 (m, 0.7H), 4.95-4.85 (m, 0.3H), 4.84-4.75 (m, 0.7H), 4.49-4.32 (m, 1H), 4.07 (t, J=4.4 Hz, 0.7H), 3.93 (s, 0.3H), 2.70-2.54 (m, 3H), 2.22 (dd, J=13.1, 8.0 Hz, 0.4H), 2.14-1.46 (m, 5.6H).

Example 249: (4-methoxy-2-(pyrimidin-2-yl)phenyl)((1S,2R,4R)-2-((5-(trifluoromethyl)pyrazin-2-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 181 substituting intermediate A-1 with intermediate A-15. MS (ESI) mass calcd. for C₂₃H₂₁F₃N₆O₂, 470.2; m/z found 471.2 [M+H]⁺. ¹H NMR (CDCl₃): 8.89-8.69 (m, 2H), 8.38-8.12 (m, 2H), 7.81-7.74 (m, 0.1H), 7.70-7.62 (m, 0.1H), 7.49-7.28 (m, 3.8H), 6.91 (dd, J=8.4, 2.6 Hz, 0.9H), 6.48-6.39 (m, 0.1H), 4.85-4.77 (m, 0.9H), 4.73-4.67 (m, 0.1H), 4.48-4.34 (m, 0.9H), 4.24 (s, 0.1H), 4.09 (d, J=5.0 Hz, 1H), 3.94-3.79 (m, 3H), 2.18 (dd, J=13.0, 8.1 Hz, 1H), 2.13-1.37 (m, 5H).

Example 250: (1H-benzo[d]imidazol-2-yl)((1S,2R,4R)-2-((5-(trifluoromethyl)pyrazin-2-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 181 substituting intermediate A-1 with 1H-benzo[d]imidazole-2-carboxylic acid. MS (ESI) mass calcd. for C₁₉H₁₇F₃N₆O, 402.1; m/z found 403.2 [M+H]⁺. ¹H NMR (CDCl₃): 8.35-7.61 (m, 3.5H), 7.40-7.13 (m, 3.5H), 6.26-5.75 (m, 1H), 5.06-4.63 (m, 1.5H), 4.27-3.95 (m, 1.5H), 2.86-2.47 (m, 1H), 2.33-1.45 (m, 5H).

Example 251: (1-methyl-1H-benzo[d]imidazol-2-yl)((1S,2R,4R)-2-((5-(trifluoromethyl)pyrazin-2-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 181 substituting intermediate A-1 with 1-methyl-1H-benzo[d]imidazole-2-carboxylic acid. MS (ESI) mass calcd. for C₂₀H₁₉F₃N₆O, 416.2; m/z found 417.2 [M+H]⁺.

Example 252: (3-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl)((1S,2R,4R)-2-((5-(trifluoromethyl)pyrazin-2-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 181 substituting intermediate A-1 with intermediate A-16. MS (ESI) mass calcd. for C₂₀H₁₇F₄N₇O, 447.1; m/z found 448.3 [M+H]⁺. ¹H NMR (CDCl₃): 8.30 (s, 0.3H), 8.19 (s, 0.7H), 7.96-7.75 (m, 2.8H), 7.58-7.49 (m, 0.3H), 7.45-7.11 (m, 3.7H), 5.83 (s, 0.2H), 4.80-4.58 (m, 1H), 4.38-4.25 (m, 0.8H), 4.24-4.13 (m, 0.2H), 4.13-4.04 (m, 0.2H), 3.97 (d, J=4.9 Hz, 0.8H), 2.22-2.07 (m, 1H), 2.07-1.40 (m, 5H).

Example 253: (4-(difluoromethoxy)-2-(2H-1,2,3-triazol-2-yl)phenyl)((1 S,2R,4R)-2-((5-(trifluoromethyl)pyrazin-2-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 181 substituting intermediate A-1 with intermediate A-23. MS (ESI) mass calcd. for C₂₁H₁₈F₅N₇O₂, 495.1; m/z found 496.3 [M+H]⁺. ¹H NMR (CDCl₃): 8.32 (s, 0.3H), 8.19 (s, 0.7H), 7.98-7.81 (m, 2.4H), 7.77 (d, J=2.3 Hz, 0.4H), 7.61 (d, J=2.4 Hz, 0.7H), 7.58-7.45 (m, 1H), 7.39 (d, J=8.4 Hz, 0.7H), 7.21 (dd, J=8.4, 2.4 Hz, 0.5H), 7.18-7.00 (m, 0.9H), 6.59 (td, J=72.6, 31.4 Hz, 1H), 6.33-6.16 (m, 0.4H), 4.92-4.70 (m, 1H), 4.43-4.19 (m, 1H), 4.09-3.83 (m, 1H), 2.30-1.44 (m, 6H).

Example 254: (3-fluoro-2-(3-methyl-1,2,4-oxadiazol-5-yl)phenyl)((1S,2R,4R)-2-((5-(trifluoromethyl)pyrazin-2-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 181 substituting intermediate A-1 with intermediate A-17. MS (ESI) mass calcd. for C₂₁H₁₈F₄N₆O₂, 462.1; m/z found 463.3 [M+H]. ¹H NMR (CDCl₃): 8.31 (s, 0.3H), 8.18 (s, 0.7H), 8.09 (s, 0.3H), 7.75-7.68 (m, 0.7H), 7.63 (td, J=8.0, 5.0 Hz, 0.3H), 7.49 (td, J=7.9, 5.1 Hz, 0.7H), 7.44-7.13 (m, 2.6H), 5.79 (d, J=8.0 Hz, 0.4H), 4.88-4.67 (m, 1H), 4.40-4.22 (m, 1H), 4.10-3.88 (m, 1H), 2.52 (s, 3H), 2.28-1.54 (m, 6H).

Example 255: (5-methoxy-2-(2H-1,2,3-triazol-2-yl)phenyl)((1S,2R,4R)-2-((5-(trifluoromethyl)pyrazin-2-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 181 substituting intermediate A-1 with intermediate A-18. MS (ESI) mass calcd. for C₂₁H₂₀F₃N₇O₂, 459.2; m/z found 460.3 [M+H]⁺. ¹H NMR (CDCl₃): 8.32 (s, 0.3H), 8.19 (s, 0.7H), 7.96-7.76 (m, 2.5H), 7.74-7.63 (m, 1H), 7.56 (s, 1H), 7.07 (dd, J=8.9, 2.9 Hz, 0.4H), 7.03-6.92 (m, 1H), 6.87 (d, J=2.9 Hz, 0.8H), 6.17-6.05 (m, 0.3H), 4.89-4.70 (m, 1H), 4.43-4.19 (m, 1H), 4.10-3.94 (m, 1H), 3.92-3.75 (m, 3H), 2.25-1.43 (m, 6H).

Example 256: (5-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl)((1S,2R,4R)-2-((5-(trifluoromethyl)pyrazin-2-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 181 substituting intermediate A-1 with intermediate A-10. MS (ESI) mass calcd. for C₂₀H₁₇F₄N₇O, 447.2; m/z found 448.3 [M+H]⁺. ¹H NMR (CDCl₃): 8.32 (s, 0.3H), 8.20 (s, 0.7H), 8.02-7.87 (m, 1.5H), 7.88-7.71 (m, 1.5H), 7.54 (s, 0.7H), 7.38-7.00 (m, 3H), 6.32-6.08 (m, 0.3H), 4.92-4.68 (m, 1H), 4.46-4.20 (m, 1H), 4.12-3.88 (m, 1H), 2.28-1.39 (m, 6H).

Example 257: (4-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl)((1S,2R,4R)-2-((5-(trifluoromethyl)pyrazin-2-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 181 substituting intermediate A-1 with intermediate A-12. MS (ESI) mass calcd. for C₂₀H₁₇F₄N₇O, 447.2; m/z found 448.3 [M+H]⁺. ¹H NMR (CDCl₃): 8.33 (s, 0.3H), 8.20 (s, 0.7H), 8.01-7.79 (m, 2.4H), 7.73 (dd, J=9.4, 2.6 Hz, 0.4H), 7.63-7.44 (m, 1.7H), 7.38 (dd, J=8.5, 5.7 Hz, 0.7H), 7.21-6.94 (m, 1.4H), 6.20 (d, J=8.5 Hz, 0.4H), 4.91-4.73 (m, 1H), 4.46-4.17 (m, 1H), 4.09-3.85 (m, 1H), 2.25-1.44 (m, 6H).

Example 258: (2-fluoro-6-(2H-1,2,3-triazol-2-yl)phenyl)((1S,2R,4R)-2-((5-(trifluoromethyl)pyrazin-2-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 181 substituting intermediate A-1 with intermediate A-11. MS (ESI) mass calcd. for C₂₀H₁₇F₄N₇O, 447.2; m/z found 448.3 [M+H]⁺. ¹H NMR (CDCl₃): 8.41-8.29 (m, 0.3H), 8.20 (s, 0.7H), 8.01-7.60 (m, 3H), 7.60-7.11 (m, 3.2H), 7.03-6.89 (m, 0.2H), 6.20-6.06 (m, 0.2H), 5.45-5.34 (m, 0.2H), 5.16-5.04 (m, 0.2H), 4.99-4.75 (m, 1H), 4.49-4.16 (m, 1H), 4.13-4.00 (m, 0.3H), 3.88 (d, J=5.2 Hz, 0.5H), 3.69 (d, J=5.1 Hz, 0.2H), 2.33-1.36 (m, 6H).

Example 259: (6-methylimidazo[2,1-b]thiazol-5-yl)((1S,2R,4R)-2-((5-(trifluoromethyl)pyrazin-2-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 181 substituting 2 intermediate A-1 with 6-methylimidazo[2,1-b]thiazole-5-carboxylic acid. MS (ESI) mass calcd. for C₁₈H₁₇F₃N₆OS, 422.2; m/z found 423.2 [M+H]⁺. ¹H NMR (CDCl₃): 8.26 (s, 1H), 7.91-7.75 (m, 2H), 6.96-6.80 (m, 1H), 5.91 (s, 1H), 4.58 (d, J=5.0 Hz, 1H), 4.42 (t, J=4.8 Hz, 1H), 4.21-4.05 (m, 1H), 2.49 (s, 3H), 2.25 (dd, J=13.2, 7.5 Hz, 1H), 2.10-1.88 (m, 2H), 1.73-1.54 (m, 3H).

Example 260: (3-fluoro-2-(oxazol-2-yl)phenyl)((1S,2R,4R)-2-((5-(trifluoromethyl)pyrazin-2-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Step A: (3-fluoro-2-iodophenyl)((1S,2R,4R)-2-((5-(trifluoromethyl)pyrazin-2-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)methanone. Prepared analogous to Example 238 substituting intermediate A-2 with 3-fluoro-2-iodobenzoic acid. MS (ESI) mass calcd. for C₁₈H₁₅F₄IN₄O, 506.0; m/z found 507.2 [M+H]⁺. ¹H NMR (CDCl₃): 8.27-8.14 (m, 1H), 8.10-7.81 (m, 1H), 7.48-7.32 (m, 0.5H), 7.23-6.83 (m, 2.5H), 6.66-5.98 (m, 1H), 4.94-4.69 (m, 1H), 4.31-4.14 (m, 0.5H), 4.08-3.90 (m, 0.5H), 3.90-3.75 (m, 0.5H), 3.72-3.44 (m, 0.5H), 2.27-1.41 (m, 6H).

Step B: (3-fluoro-2-(oxazol-2-yl)phenyl)((1S,2R,4R)-2-((5-(trifluoromethyl)pyrazin-2-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)methanone. The title compound of step A (35 mg) and 2-(tributylstannyl)oxazole (17 μL) were dissolved in DME (1 mL). The solution was degassed with N₂ as CuI (1 mg) and Pd(PPh₃)₄ (4 mg) was added. The reaction was heated at 120° C. for 3 h. Additional CuI and Pd(PPh₃)₄ and the reaction purged with N₂. Heating was continued overnight. The reaction was cooled to rt, filtered through a pad of celite and purified via prep HPLC to give the title compound (12 mg, 39%). MS (ESI) mass calcd. for C₂₁H₁₇F₄N₅O₂, 447.1; m/z found 448.3 [M+H]⁺. ¹H NMR (CDCl₃): 8.34 (s, 1H), 8.16 (s, 1H), 7.98-7.78 (m, 1H), 7.69 (s, 0.8H), 7.60-7.06 (m, 4H), 6.80-6.61 (m, 0.2H), 4.92-4.66 (m, 1H), 4.46-4.23 (m, 1H), 4.06-3.80 (m, 1H), 2.36-1.51 (m, 6H).

Example 261: (2-((4,6-dimethylpyrimidin-2-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)(3-fluoro-2-methoxyphenyl)methanone

Example 262: (3-fluoro-2-(pyridazin-3-yl)phenyl)((1S,2R,4R)-2-((5-(trifluoromethyl)pyrazin-2-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 260 substituting 2-(tributylstannyl)oxazole with 3-(tributylstannyl)pyridazine. MS (ESI) mass calcd. for C₂₂H₁₈F₄N₆O, 458.1; m/z found 459.1 [M+H]⁺. ¹H NMR (500 MHz, Chloroform-d) 9.25-9.14 (m, 1H), 8.50 (s, 0.5H), 8.28 (s, 0.8H), 8.17 (s, 0.5H), 7.97-7.80 (m, 1.5H), 7.72-7.59 (m, 1H), 7.55-7.41 (m, 1H), 7.34-7.18 (m, 2.2H), 6.96 (d, J=8.1 Hz, 0.5H), 4.79-4.72 (m, 0.55H), 4.71-4.64 (m, 0.45H), 4.53-4.43 (m, 0.6H), 4.38-4.28 (m, 0.45H), 4.18 (s, 0.4H), 4.13-4.05 (m, 0.55H), 2.30-1.47 (m, 6H).

Example 263: (3-methyl-2-(pyridazin-3-yl)phenyl)((1S,2R,4R)-2-((5-(trifluoromethyl)pyrazin-2-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Step A: (2-iodo-3-methylphenyl)((1S,2R,4R)-2-((5-(trifluoromethyl)pyrazin-2-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)methanone. Prepared analogous to Example 238 substituting intermediate A-2 with 2-iodo-3-methylbenzoic acid. MS (ESI) mass calcd. for C₁₉H₁₈F₃IN₄O, 502.0; m/z found 503.0 [M+H]⁺. ¹H NMR (400 MHz, Chloroform-d) 8.26-8.03 (m, 1.4H), 7.88-6.60 (m, 4.6H), 4.93-4.58 (m, 1H), 4.32-4.15 (m, 0.4H), 3.92 (s, 0.4H), 3.86-3.76 (m, 0.6H), 3.57 (s, 0.6H), 2.51 (s, 1.4H), 2.40 (s, 1.6H), 2.21-0.66 (m, 6H).

Step B: (3-methyl-2-(pyridazin-3-yl)phenyl)((1S,2R,4R)-2-((5-(trifluoromethyl)pyrazin-2-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)methanone. Prepared analogous to Example 260 Step B substituting 2-(tributylstannyl)oxazole with 3-(tributylstannyl)pyridazine. MS (ESI) mass calcd. for C₂₃H₂₁F₃N₆O, 454.2; m/z found 455.2 [M+H]⁺. ¹H NMR (400 MHz, Chloroform-d) 9.22 (dd, J=4.9, 1.7 Hz, 0.25H), 9.19 (dd, J=4.8, 1.8 Hz, 0.75H), 8.57 (s, 0.75H), 8.27 (s, 0.25H), 8.21 (s, 0.25H), 8.16 (s, 0.75H), 7.97 (s, 0.75H), 7.72-7.56 (m, 2H), 7.44-7.27 (m, 2.25H), 7.25-7.19 (m, 0.75H), 6.40 (d, J=8.0 Hz, 0.25H), 4.68-4.62 (m, 0.75H), 4.59-4.54 (m, 0.25H), 4.39 (ddd, J=9.3, 8.1, 3.9 Hz, 0.75H), 4.28-4.15 (m, 0.5H), 4.08-4.03 (m, 0.75H), 2.32 (s, 0.75H), 2.21 (s, 2.25H), 2.18-1.42 (m, 6H).

Example 264 (3-fluoro-2-(pyridazin-4-yl)phenyl)((1S,2R,4R)-2-((5-(trifluoromethyl)pyrazin-2-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 260 substituting 2-(tributylstannyl)oxazole with 4-(tributylstannyl)pyridazine. MS (ESI) mass calcd. for C₂₂H₁₈F₄N₆O, 458.1; m/z found 459.2 [M+H]⁺. ¹H NMR (400 MHz, Chloroform-d) 9.38-9.20 (m, 2H), 8.28 (s, 0.6H), 8.19 (s, 0.4H), 8.00 (s, 0.6H), 7.94 (s, 0.4H), 7.71-7.63 (m, 0.6H), 7.62-7.50 (m, 1H), 7.40-7.29 (m, 1H), 7.24-7.08 (m, 1.4H), 5.24 (s, 0.4H), 4.80 (s, 0.6H), 4.67 (s, 0.4H), 4.61 (d, J=5.3 Hz, 0.6H), 4.02-3.92 (m, 0.6H), 3.85-3.75 (m, 0.4H), 3.70-3.59 (m, 1H), 1.90-2.07 (m, 1H), 1.84-0.79 (m, 5H).

Example 265 (3-fluoro-2-(pyrazin-2-yl)phenyl)((1S,2R,4R)-2-((5-(trifluoromethyl)pyrazin-2-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 260 substituting 2-(tributylstannyl)oxazole with 2-(tributylstannyl)pyrazine. MS (ESI) mass calcd. for C₂₂H₁₈F₄N₆O, 458.1; m/z found 459.2 [M+H]⁺. ¹H NMR (400 MHz, Chloroform-d) 8.99-8.94 (m, 1H), 8.69 (d, J=2.6 Hz, 1H), 8.58-8.51 (m, 1H), 8.19 (s, 1H), 8.03 (s, 1H), 7.57 (s, 1H), 7.44-7.37 (m, 1H), 7.25-7.20 (m, 2H), 4.80-4.74 (m, 1H), 4.40 (td, J=8.6, 3.6 Hz, 1H), 4.05 (d, J=5.1 Hz, 1H), 2.24-2.16 (m, 1H), 1.78-1.67 (m, 2H), 1.62-1.51 (m, 2H), 1.41-1.29 (m, 1H).

Example 266 (3-methyl-2-(oxazol-2-yl)phenyl)((1S,2R,4R)-2-((5-(trifluoromethyl)pyrazin-2-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 263 substituting 3-(tributylstannyl)pyridazine with 2-(tributylstannyl)oxazole. MS (ESI) mass calcd. for C₂₂H₂₀F₃N₅O₂, 443.2; m/z found 444.2 [M+H]⁺. ¹H NMR (500 MHz, Chloroform-d) 8.57 (s, 1H), 8.14 (s, 1H), 7.88 (d, J=0.9 Hz, 1H), 7.79 (d, J=1.4 Hz, 1H), 7.33-7.23 (m, 3H), 7.20-7.14 (m, 1H), 4.82-4.75 (m, 1H), 4.29 (td, J=8.5, 3.7 Hz, 1H), 3.94 (d, J=4.9 Hz, 1H), 2.28 (s, 3H), 2.16-1.45 (m, 6H).

Example 267 (4-fluoro-2-(pyrimidin-2-yl)phenyl)((1S,2R,4R)-2-((5-(trifluoromethyl)pyrazin-2-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 238 substituting intermediate A-2 with intermediate A-25. MS (ESI) mass calcd. for: C₂₂H₁₈F₄N₆O, 458.1; m/z found 459.2 [M+H]⁺. ¹H NMR (500 MHz, Chloroform-d) 8.89-8.81 (m, 1.7H), 8.80-8.73 (m, 0.3H), 8.33-7.87 (m, 2H), 7.80 (s, 0.2H), 7.74-7.66 (m, 0.8H), 7.56-7.31 (m, 2.8H), 7.21-7.14 (m, 0.2H), 7.14-7.06 (m, 0.8H), 6.58 (s, 0.2H), 4.88-4.78 (m, 0.8H), 4.72 (d, J=5.2 Hz, 0.2H), 4.40 (s, 0.8H), 4.26 (s, 0.2H), 4.10-3.97 (m, 1H), 2.27-1.39 (m, 6H).

Example 268 (3-fluoro-2-(pyridin-4-yl)phenyl)((1S,2R,4R)-2-((5-(trifluoromethyl)pyrazin-2-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 260 substituting 2-(tributylstannyl)oxazole with 4-(tributylstannyl)pyridine. MS (ESI) mass calcd. for: C₂₃H₁₉F₄N₅O, 457.2; m/z found 458.2 [M+H]⁺. ¹H NMR (500 MHz, Chloroform-d) 8.78-8.61 (m, 2H), 8.28 (s, 0.6H), 8.15 (s, 0.4H), 7.87 (s, 1H), 7.72-7.28 (m, 4.2H), 7.23-7.02 (m, 1.4H), 5.49 (s, 0.4H), 4.67-4.60 (m, 0.4H), 4.56 (d, J=5.3 Hz, 0.6H), 3.99-3.89 (m, 0.6H), 3.82-3.72 (m, 0.4H), 3.65-3.58 (m, 0.6H), 3.56 (d, J=5.4 Hz, 0.4H), 2.00-0.80 (m, 6H).

Example 269 (3-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl)((1S,2R,4R)-2-((5-(trifluoromethyl)pyrimidin-2-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Step A: (1S,2R,4R)-tert-butyl 2-((5-(trifluoromethyl)pyrimidin-2-yl)amino)-7-azabicyclo[2.2.1]heptane-7-carboxylate. To intermediate B-5 (250 mg, 1.2 mmol) and K₂CO₃ (244 mg, 1.8 mmol) in DMF (1.7 mL) was added 2-chloro-5-(trifluoromethyl)pyrimidine (258 mg, 1.4 mmol). After heating at 70° C. for 17 h, the mixture was cooled to rt, diluted with EtOAc and H₂O. The aqueous layer was extracted with EtOAc (3×). The combined organics were washed with 4% MgSO₄ (aq) and dried (MgSO₄). Purification via silica gel chromatography (0-30% EtOAc in hexanes) gave the title compound (356 mg, 84%). MS (ESI) mass calcd. for C₁₆H₂₁F₃N₄O₂, 358.2; m/z found 359.2 [M+H]⁺. ¹H NMR (500 MHz, Chloroform-d) 8.58-8.37 (m, 2H), 5.70 (s, 1H), 4.30 (s, 1H), 1.78-1.68 (m, 1H), 4.25-4.17 (m, 1H), 1.89-1.79 (m, 1H), 4.12-4.03 (m, 1H), 2.03 (dd, J=13.1, 7.8 Hz, 1H), 1.63-1.37 (m, 12H).

Step B: (1S,2R,4R)—N-(5-(trifluoromethyl)pyrimidin-2-yl)-7-azabicyclo[2.2.1]heptan-2-amine. To the title compound of step A (355 mg, 1 mmol) in DCM (9.7 mL) was added 4M HCl in dioxane (1.2 mL). The reaction was allowed to proceed overnight then concentrated and neutralized with 5% Na₂CO₃ (aq) and extracted with DCM (2×). The combined organics were dried (Na₂SO₄) to give the title compound of step B that was used without further purification.

Step C: (3-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl)((1S,2R,4R)-2-((5-(trifluoromethyl)pyrimidin-2-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)methanone. To the title compound of step B (25 mg, 0.1 mmol) in DCM (1 mL) was added DIPEA (22 μL, 0.13 mmol) and intermediate A-16 (22 mg, 0.1 mmol). Then T3P (50% solution in DMF, 0.17 mL, 0.29 mmol) was added dropwise and the reaction heated at 45° C. for 12 h. After allowing to cool to rt, DCM was added and the mixture washed with H₂O then saturated NaHCO₃ (aq). The combined aq layers were extracted with DCM. The combined organic layers were dried (Na₂SO₄). Purification was performed using Agilent prep method X to give the title compound (35 mg, 80%). MS (ESI) mass calcd. for: C₂₀H₁₇F₄N₇O, 447.1; m/z found 448.2 [M+H]⁺. ¹H NMR (400 MHz, Chloroform-d) 8.50 (s, 0.9H), 8.41 (s, 1.1H), 8.09 (s, 0.9H), 7.95 (s, 1.1H), 7.56-7.47 (m, 0.5H), 7.44-7.32 (m, 1H), 7.33-7.23 (m, 1.5H), 7.20-7.14 (m, 0.5H), 6.18 (d, J=8.6 Hz, 0.5H), 4.83-4.74 (m, 0.5H), 4.67 (d, J=5.2 Hz, 0.5H), 4.34-4.19 (m, 1H), 4.11-4.04 (m, 0.5H), 3.99 (d, J=4.8 Hz, 0.5H), 2.21-1.44 (m, 6H).

Example 270 ((1S,2R,4R)-2-((3-bromoimidazo[1,2-a]pyrazin-8-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)(3-fluoro-2-(pyrimidin-2-yl)phenyl)methanone

Step A: (1S,2R,4R)-tert-butyl 2-((3-bromoimidazo[1,2-a]pyrazin-8-yl)amino)-7-azabicyclo[2.2.1]heptane-7-carboxylate. Prepared analogous to Example 269 step A substituting 2-chloro-5-(trifluoromethyl)pyrimidine with 3-bromo-8-chloroimidazo[1,2-a]pyrazine. MS (ESI) mass calcd. for: C₁₇H₂₂BrN₅O₂, 407.1; m/z found 408.1 [M+H]⁺. ¹H NMR (500 MHz, Chloroform-d) 7.45 (s, 1H), 7.43 (d, J=4.7 Hz, 1H), 7.40 (d, J=4.7 Hz, 1H), 6.15 (s, 1H), 4.37-4.27 (m, 2H), 4.27-4.21 (m, 1H), 2.08 (dd, J=13.0, 7.8 Hz, 1H), 1.90-1.33 (m, 14H).

Step B: N-((1S,2R,4R)-7-azabicyclo[2.2.1]heptan-2-yl)-3-bromoimidazo[1,2-a]pyrazin-8-amine. Prepared analogous to Example 269 step B using title compound of step A.

Step C: ((1S,2R,4R)-2-((3-bromoimidazo[1,2-a]pyrazin-8-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)(3-fluoro-2-(pyrimidin-2-yl)phenyl)methanone. Prepared analogous to Example 269 step C substituting intermediate A-16 with intermediate A-2. MS (ESI) mass calcd. for: C₂₃H₁₉BrFN₇O, 507.1; m/z found 508.1 [M+H]⁺. ¹H NMR (400 MHz, Chloroform-d) 8.92 (d, J=4.9 Hz, 0.7H), 8.88 (d, J=4.9 Hz, 1.3H), 7.53-7.03 (m, 7.6H), 5.82 (d, J=7.6 Hz, 0.4H), 4.81-4.75 (m, 0.6H), 4.71 (d, J=5.1 Hz, 0.4H), 4.47-4.37 (m, 0.6H), 4.31-4.22 (m, 0.4H), 4.13-4.07 (m, 0.6H), 4.06-3.99 (m, 0.4H), 2.26-1.36 (m, 6H).

Example 271 (3-fluoro-2-(pyrimidin-2-yl)phenyl)((1S,2R,4R)-2-((5-(trifluoromethyl)pyrimidin-2-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 269 substituting intermediate A-16 with intermediate A-2. MS (ESI) mass calcd. for: C₂₂H₁₈F₄N₆O, 458.1; m/z found 459.2 [M+H]⁺. ¹H NMR (400 MHz, Chloroform-d) 8.90 (d, J=5.0 Hz, 2H), 8.49 (s, 1H), 8.44-8.31 (m, 2H), 7.43-7.32 (m, 2H), 7.26-7.14 (m, 2H), 4.80-4.75 (m, 1H), 4.45-4.37 (m, 1H), 4.09 (d, J=5.0 Hz, 1H), 2.22 (dd, J=12.9, 8.0 Hz, 1H), 2.11-1.51 (m, 5H).

Example 272 (3-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl)((1S,2R,4R)-2-((5-(trifluoromethyl)pyrimidin-2-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 269 substituting intermediate A-16 with intermediate A-24. MS (ESI) mass calcd. for: C₂₁H₂₀F₃N₇O, 443.2; m/z found 444.2 [M+H]. ¹H NMR (400 MHz, Chloroform-d) 8.49 (s, 0.8H), 8.41 (s, 1.2H), 8.02 (s, 0.8H), 7.91 (s, 1.2H), 7.47-7.39 (m, 1H), 7.38-7.28 (m, 2H), 7.23-7.16 (m, 0.6H), 5.98 (d, J=8.4 Hz, 0.4H), 4.77-4.68 (m, 0.6H), 4.60 (d, J=5.1 Hz, 0.4H), 4.29-4.17 (m, 1H), 4.11-4.03 (m, 0.4H), 3.99 (d, J=5.0 Hz, 0.6H), 2.27 (s, 1.3H), 2.24 (s, 1.7H), 2.18-1.41 (m, 6H).

Example 273 (3-methyl-2-(pyrimidin-2-yl)phenyl)((1S,2R,4R)-2-((5-(trifluoromethyl)pyrazin-2-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 238 substituting intermediate A-2 with intermediate A-26. MS (ESI) mass calcd. for: C₂₃H₂₁F₃N₆O, 454.2; m/z found 455.1 [M+H]⁺. ¹H NMR (400 MHz, Chloroform-d) 8.85 (d, J=5.0 Hz, 2H), 8.50 (d, J=9.2 Hz, 1H), 8.17 (s, 1H), 7.66 (d, J=1.3 Hz, 1H), 7.37 (t, J=5.0 Hz, 1H), 7.31-7.18 (m, 3H), 4.73-4.67 (m, 1H), 4.35 (td, J=8.7, 3.7 Hz, 1H), 4.14-4.09 (m, 1H), 2.29 (s, 3H), 2.19-1.45 (m, 6H).

Example 274 (3-fluoro-2-(pyrimidin-2-yl)phenyl)((1S,2R,4R)-2-((3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyrazin-8-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Step A: (1S,2R,4R)-tert-butyl 2-((3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyrazin-8-yl)amino)-7-azabicyclo[2.2.1]heptane-7-carboxylate. Prepared analogous to Example 269 step A substituting 2-chloro-5-(trifluoromethyl)pyrimidine with 8-chloro-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyrazine. MS (ESI) mass calcd. for: C₁₇H₂₁F₃N₆O₂, 398.2; m/z found 399.2 [M+H]⁺. ¹H NMR (500 MHz, Chloroform-d) 7.51-7.48 (m, 1H), 7.48-7.45 (m, 1H), 6.58 (d, J=7.6 Hz, 1H), 4.41-4.25 (m, 3H), 1.94-1.83 (m, 1H), 2.12 (dd, J=13.1, 7.8 Hz, 1H), 1.83-1.70 (m, 2H), 1.59-1.52 (m, 1H), 1.50-1.41 (m, 10H).

Step B: N-((1S,2R,4R)-7-azabicyclo[2.2.1]heptan-2-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyrazin-8-amine. Prepared analogous to Example 269 step B using title compound of step A.

Step C: (3-fluoro-2-(pyrimidin-2-yl)phenyl)((1S,2R,4R)-2-((3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyrazin-8-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)methanone. Prepared analogous to Example 269 step C substituting intermediate A-16 with intermediate A-2. MS (ESI) mass calcd. for: C₂₃H₁₈F₄N₈O, 498.2; m/z found 499.2 [M+H]⁺. ¹H NMR (400 MHz, Chloroform-d) 8.99 (d, J=4.9 Hz, 0.6H), 8.95 (d, J=5.0 Hz, 1.4H), 8.72 (s, 0.7H), 7.55-7.28 (m, 4.6H), 7.21-7.10 (m, 1.4H), 6.18 (d, J=7.5 Hz, 0.3H), 4.88-4.80 (m, 0.7H), 4.75 (d, J=5.1 Hz, 0.3H), 4.67 (s, 0.7H), 4.33 (s, 0.3H), 4.16-4.06 (m, 1H), 2.27 (dd, J=12.7, 8.2 Hz, 0.7H), 2.11 (dd, J=13.0, 8.1 Hz, 0.3H), 2.04-1.41 (m, 5H).

Example 275 methyl 5-(((1S,2R,4R)-7-(3-fluoro-2-(pyrimidin-2-yl)benzoyl)-7-azabicyclo[2.2.1]heptan-2-yl)amino)pyrazine-2-carboxylate

Step A: (1S,2R,4R)-tert-butyl 2-((5-(methoxycarbonyl)pyrazin-2-yl)amino)-7-azabicyclo[2.2.1]heptane-7-carboxylate. Prepared analogous to Example 269 step A substituting 2-chloro-5-(trifluoromethyl)pyrimidine with methyl 5-chloropyrazine-2-carboxylate. MS (ESI) mass calcd. for: C₁₇H₂₄N₄O₄, 348.2; m/z found 349.2 [M+H]⁺. ¹H NMR (400 MHz, Chloroform-d) 8.77 (d, J=1.4 Hz, 1H), 7.88 (d, J=1.4 Hz, 1H), 5.55 (s, 1H), 4.34-4.27 (m, 1H), 4.25-4.18 (m, 1H), 4.12-4.06 (m, 1H), 3.95 (s, 3H), 2.12-2.05 (m, 1H), 1.92-1.72 (m, 2H), 1.63-1.38 (m, 12H).

Step B: methyl 5-((1S,2R,4R)-7-azabicyclo[2.2.1]heptan-2-ylamino)pyrazine-2-carboxylate. Prepared analogous to Example 269 step B using title compound of step A.

Step C: methyl 5-(((1S,2R,4R)-7-(3-fluoro-2-(pyrimidin-2-yl)benzoyl)-7-azabicyclo[2.2.1]heptan-2-yl)amino)pyrazine-2-carboxylate. Prepared analogous to Example 269 step C substituting intermediate A-16 with intermediate A-2. MS (ESI) mass calcd. for: C₂₃H₂₁FN₆O₃, 448.2; m/z found 449.2 [M+H]⁺. ¹H NMR (500 MHz, Chloroform-d) 8.87 (d, J=4.9 Hz, 2H), 8.65 (s, 1H), 8.37 (d, J=9.4 Hz, 1H), 7.67 (s, 1H), 7.42-7.34 (m, 2H), 7.24-7.17 (m, 2H), 4.77-4.70 (m, 1H), 4.48-4.39 (m, 1H), 4.07 (d, J=5.1 Hz, 1H), 3.90 (s, 3H), 2.18 (dd, J=13.0, 8.1 Hz, 1H), 2.11-2.00 (m, 1H), 1.97-1.62 (m, 3H), 1.58-1.48 (m, 1H).

Example 276 (2-iodo-3-methylphenyl)((1S,2R,4R)-2-((5-(trifluoromethyl)pyrimidin-2-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 269 substituting intermediate A-16 with 2-iodo-3-methylbenzoic acid. MS (ESI) mass calcd. for: C₁₉H₁₈F₃IN₄O, 502.0; m/z found 503.0 [M+H]⁺. ¹H NMR (400 MHz, Chloroform-d) 8.59-8.30 (m, 2H), 7.32-7.22 (m, 1.4H), 7.19-6.96 (m, 1H), 6.93-6.83 (m, 0.6H), 6.02 (s, 0.5H), 5.54 (s, 0.5H), 5.01-4.91 (m, 0.5H), 4.84 (d, J=5.1 Hz, 0.5H), 4.28 (s, 0.5H), 4.02 (s, 0.5H), 3.84-3.66 (m, 1H), 2.50 (s, 1.5H), 2.43 (s, 1.5H), 2.24-1.39 (m, 6H).

Example 277 (3-fluoro-2-iodophenyl)((1S,2R,4R)-2-((5-(trifluoromethyl)pyrimidin-2-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 269 substituting intermediate A-16 with 3-fluoro-2-iodobenzoic acid. MS (ESI) mass calcd. for: C₁₈H₁₅F₄IN₄O, 506.0; m/z found 507.0 [M+H]⁺. ¹H NMR (400 MHz, Chloroform-d) 8.57-8.33 (m, 2H), 7.42-7.32 (m, 0.5H), 7.16-7.02 (m, 1.5H), 6.99-6.88 (m, 1H), 5.99 (d, J=7.6 Hz, 0.5H), 5.55 (s, 0.5H), 5.00-4.91 (m, 0.5H), 4.85 (d, J=5.3 Hz, 0.5H), 4.32-4.24 (m, 0.5H), 4.05-3.97 (m, 0.5H), 3.81-3.71 (m, 1H), 2.22-1.93 (m, 2H), 1.91-1.43 (m, 4H).

Example 278 (3-fluoro-2-(pyrimidin-2-yl)phenyl)((1S,2R,4R)-2-((5-methylpyrazin-2-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Step A: (1S,2R,4R)-tert-butyl 2-((5-methylpyrazin-2-yl)amino)-7-azabicyclo[2.2.1]heptane-7-carboxylate. Prepared analogous to Example 279 step A substituting 2-chloro-5-(trifluoromethyl)pyridine with 2-chloro-5-methylpyrazine. MS (ESI) mass calcd. for: C₁₆H₂₄N₄O₂, 304.2; m/z found 305.2 [M+H]⁺. ¹H NMR (400 MHz, Chloroform-d) 7.86 (s, 1H), 7.78 (d, J=1.5 Hz, 1H), 4.71 (s, 1H), 4.28 (s, 1H), 4.19 (d, J=4.9 Hz, 1H), 3.95-3.85 (m, 1H), 2.38 (s, 3H), 2.11-1.96 (m, 1H), 1.89-1.66 (m, 2H), 1.58-1.33 (m, 12H).

Step B: (1S,2R,4R)—N-(5-methylpyrazin-2-yl)-7-azabicyclo[2.2.1]heptan-2-amine. Prepared analogous to Example 279 step B using title compound of step A.

Step C: (3-fluoro-2-(pyrimidin-2-yl)phenyl)((1S,2R,4R)-2-((5-methylpyrazin-2-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)methanone. Prepared analogous to Example 279 step C. MS (ESI) mass calcd. for: C₂₂H₂₁FN₆O, 404.2; m/z found 405.2 [M+H]⁺. ¹H NMR (500 MHz, Chloroform-d) 8.87 (d, J=5.0 Hz, 2H), 7.74 (s, 1H), 7.60 (s, 1H), 7.41-7.30 (m, 3H), 7.23-7.12 (m, 2H), 4.76-4.68 (m, 1H), 4.30-4.17 (m, 1H), 4.08-4.01 (m, 1H), 2.30 (s, 3H), 2.15 (dd, J=12.9, 8.1 Hz, 1H), 2.07-1.95 (m, 1H), 1.95-1.84 (m, 1H), 1.74-1.46 (m, 3H).

Example 279 (3-fluoro-2-(pyrimidin-2-yl)phenyl)((1S,2R,4R)-2-((5-(trifluoromethyl)pyridin-2-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Step A: (1S,2R,4R)-tert-butyl 2-((5-(trifluoromethyl)pyridin-2-yl)amino)-7-azabicyclo[2.2.1]heptane-7-carboxylate. In a microwave vial, toluene (8.3 mL) was degassed with N₂ for 10 minutes then Pd(OAc)₂ (22 mg, 0.03 mmol) and racemic BINAP (21 mg, 0.03 mmol) were added and the solution was degassed with N₂ for 5 minutes. Then intermediate B-5, 2-chloro-5-(trifluoromethyl)pyridine (150 mg, 0.83 mmol) and sodium tert-butoxide (115 mg, 1.16 mmol) were added and the reaction mixture was stirred at 70° C. After 15 h the reaction mixture was filtered through a pad of celite and solvent was evaporated. Purification via silica gel chromatography (0-40% EtOAc in hexanes) gave the title compound of step A (192 mg, 65%). MS (ESI) mass calcd. for: C₁₇H₂₂F₃N₃O₂, 357.2; m/z found 358.2 [M+H]⁺. ¹H NMR (500 MHz, Chloroform-d) 8.33 (s, 1H), 7.61-7.49 (m, 1H), 6.35 (d, J=8.8 Hz, 1H), 5.06 (s, 1H), 4.29 (s, 1H), 4.20 (s, 1H), 4.03-3.91 (m, 1H), 2.04 (dd, J=13.0, 7.6 Hz, 1H), 1.89-1.79 (m, 1H), 1.79-1.71 (m, 1H), 1.59-1.37 (m, 12H).

Step B: (1S,2R,4R)—N-(5-(trifluoromethyl)pyridin-2-yl)-7-azabicyclo[2.2.1]heptan-2-amine. To the title compound of step A (319 mg, 0.89 mmol) in DCM (8.7 mL) was added 4M HCl in dioxane (1.1 mL). The reaction was allowed to proceed overnight then concentrated and neutralized with 5% Na₂CO₃ (aq) and extracted with DCM (2×). The combined organics were dried (Na₂SO₄) to give the title compound of step B that was used without further purification.

Step C: (3-fluoro-2-(pyrimidin-2-yl)phenyl)((1S,2R,4R)-2-((5-(trifluoromethyl)pyridin-2-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)methanone. To the title compound of step B (100 mg, 0.39 mmol) in DCM (3.9 mL) was added DIPEA (87 μL, 0.51 mmol) and intermediate A-2 (100 mg, 0.43 mmol). Then T3P (50% solution in DMF, 0.7 mL, 1.16 mmol) was added dropwise and the reaction heated at 45° C. for 12 h. After allowing to cool to rt, DCM was added and the mixture washed with H₂O then saturated NaHCO₃ (aq). The combined aq layers were extracted with DCM. The combined organic layers were dried (Na₂SO₄). Purification was performed using Agilent prep method X to give the title compound (61 mg, 34%). MS (ESI) mass calcd. for: C₂₃H₁₉F₄N₅O, 457.2; m/z found 458.2 [M+H]⁺. ¹H NMR (400 MHz, Chloroform-d) 8.88 (d, J=4.9 Hz, 2H), 8.22 (s, 1H), 7.67 (d, J=9.3 Hz, 1H), 7.43-7.28 (m, 3H), 7.24-7.12 (m, 2H), 6.19 (d, J=8.8 Hz, 1H), 4.76-4.68 (m, 1H), 4.43-4.32 (m, 1H), 4.08 (d, J=5.0 Hz, 1H), 2.16 (dd, J=12.9, 8.1 Hz, 1H), 2.08-1.83 (m, 2H), 1.77-1.38 (m, 3H).

Example 280 (4-fluoro-2-(pyrimidin-2-yl)phenyl)((1S,2R,4R)-2-((5-(trifluoromethyl)pyridin-2-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 279 substituting intermediate A-2 with intermediate A-25. MS (ESI) mass calcd. for: C₂₃H₁₉F₄N₅O, 457.2; m/z found 458.2 [M+H]⁺. ¹H NMR (400 MHz, Chloroform-d) 8.89-8.76 (m, 2H), 8.36 (s, 0.2H), 8.26-8.19 (m, 0.8H), 8.05-7.91 (m, 0.4H), 7.70 (dd, J=9.3, 2.7 Hz, 0.6H), 7.60-7.53 (m, 0.3H), 7.48-7.40 (m, 0.3H), 7.40-7.28 (m, 2.6H), 7.25-6.99 (m, 1.6H), 6.36 (d, J=8.7 Hz, 0.2H), 5.96 (d, J=8.8 Hz, 0.8H), 5.70 (s, 0.2H), 4.87-4.80 (m, 0.8H), 4.73 (d, J=5.3 Hz, 0.2H), 4.38 (s, 0.8H), 4.17 (s, 0.2H), 4.06-4.00 (m, 0.8H), 4.00-3.94 (m, 0.2H), 2.21 (dd, J=12.9, 8.0 Hz, 0.8H), 2.12-1.35 (m, 5.2H).

Example 281 (3-methyl-2-(pyrimidin-2-yl)phenyl)((1S,2R,4R)-2-((5-(trifluoromethyl)pyrimidin-2-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 269 substituting intermediate A-16 with intermediate A-26. MS (ESI) mass calcd. for: C₂₃H₂₁F₃N₆O, 454.2; m/z found 455.3 [M+H]⁺. ¹H NMR (500 MHz, Chloroform-d) 8.89-8.85 (m, 2H), 8.70 (s, 1H), 8.44-8.32 (m, 2H), 7.34-7.23 (m, 3H), 7.21-7.15 (m, 1H), 4.77-4.68 (m, 1H), 4.43-4.33 (m, 1H), 4.11 (d, J=5.1 Hz, 1H), 2.36 (s, 3H), 2.19 (dd, J=12.8, 7.9 Hz, 1H), 2.09-1.99 (m, 1H), 1.94-1.85 (m, 1H), 1.72-1.48 (m, 3H).

Example 282 (3-fluoro-2-(pyrimidin-2-yl)phenyl)((1S,2R,4R)-2-(methyl(5-(trifluoromethyl)pyrazin-2-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

The title compound of Example 238 (63 mg, 0.14 mmol) was dissolved in DMF (1.4 mL) and then sodium tert-butoxide (15 mg, 0.15 mmol) followed by iodomethane (9 μL, 0.14 mmol) were added. After 15 h at room temperature the reaction mixture was diluted with EtOAc and water was added. The aqueous phase was extracted twice with EtOAc and the combined organic phases were dried over MgSO₄, filtered and evaporated. Purification was performed using Agilent prep method X to give the title compound (40 mg, 62%). MS (ESI) mass calcd. for: C₂₃H₂₀F₄N₆O, 472.2; m/z found 473.2 [M+H]⁺. ¹H NMR (500 MHz, Chloroform-d) 8.81 (d, J=4.9 Hz, 2H), 8.35 (s, 1H), 8.02 (s, 1H), 7.55-7.46 (m, 1H), 7.34-7.20 (m, 3H), 4.81-4.73 (m, 1H), 4.67 (d, J=4.3 Hz, 1H), 4.17-4.08 (m, 1H), 3.05 (s, 3H), 2.12 (dd, J=12.8, 8.3 Hz, 1H), 1.98-1.44 (m, 5H).

Example 283 (3-methyl-2-(oxazol-2-yl)phenyl)((1S,2R,4R)-2-((5-(trifluoromethyl)pyrimidin-2-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 269 substituting intermediate A-16 with intermediate A-31. MS (ESI) mass calcd. for: C₂₂H₂₀F₃N₅O₂, 443.2; m/z found 444.1 [M+H]⁺. ¹H NMR (400 MHz, Chloroform-d) 8.48 (s, 1H), 8.35 (s, 1H), 7.88-7.78 (m, 1H), 7.68 (s, 0.4H), 7.44-7.21 (m, 3.6H), 7.15 (dd, J=6.6, 2.2 Hz, 0.6H), 7.06-6.97 (m, 0.4H), 4.84-4.78 (m, 0.6H), 4.73-4.67 (m, 0.4H), 4.33 (td, J=8.4, 3.0 Hz, 0.4H), 4.24 (td, J=8.2, 3.7 Hz, 0.6H), 4.04-3.98 (m, 0.4H), 3.97-3.89 (m, 0.6H), 2.47 (s, 1.7H), 2.37 (s, 1.3H), 2.19-1.41 (m, 6H).

Example 284 (3-fluoro-2-(oxazol-2-yl)phenyl)((1S,2R,4R)-2-((5-(trifluoromethyl)pyrimidin-2-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

In a microwave vial was dissolved the title compound of Example 277 (30 mg, 0.06 mmol) and 2-(tributylstannyl)oxazole (15 μL, 0.07 mmol) in DME (1 mL). The solution was degassed with N₂ for 5 minutes then CuI (1 mg, 0.0045 mmol) and Pd(PPh₃)₄ (5 mg, 0.0045 mmol) were added. The reaction was purged with N₂ and heated at 145° C. for 3 h. The reaction was cooled to rt, filtered through a pad of celite and purified via prep HPLC to give the title compound (19 mg, 72%). MS (ESI) mass calcd. for: C₂₁H₁₇F₄N₅O₂, 447.1; m/z found 448.1 [M+H]⁺. ¹H NMR (500 MHz, Chloroform-d) 8.49 (s, 1H), 8.36 (s, 0.8H), 7.85 (s, 0.8H), 7.76 (s, 0.4H), 7.62-7.45 (m, 1H), 7.43-7.33 (m, 1H), 7.32-7.23 (m, 2H), 7.23-7.09 (m, 1H), 4.91-4.85 (m, 0.4H), 4.78 (d, J=5.4 Hz, 0.6H), 4.42 (td, J=8.6, 2.8 Hz, 0.6H), 4.28 (td, J=8.2, 3.6 Hz, 0.4H), 4.00-3.95 (m, 0.6H), 3.89 (d, J=4.4 Hz, 0.4H), 2.23-1.44 (m, 6H).

Example 285 (±)-(3-fluoro-2-(pyrimidin-2-yl)phenyl)(2-((5-(trifluoromethyl)pyrimidin-2-yl)oxy)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Step A: (±)-tert-butyl 2-((5-(trifluoromethyl)pyrimidin-2-yl)oxy)-7-azabicyclo[2.2.1]heptane-7-carboxylate: To (±)-tert-butyl 2-hydroxy-7-azabicyclo[2.2.1]heptane-7-carboxylate (exo) (52 mg, 0.25 mol) in DMF (5 mL) was added 60 wt % NaH (20 mg, 0.5 mmol) in one portion. The reaction was heated at 80° C. for 5 min, then 2-chloro-5-(trifluoromethyl)pyrimidine (89.7 mg, 0.49 mmol) was added. After heating at 80° C. for 2 hours, water was added and the mixture extracted with DCM (3×). The combined organics were dried (Na₂SO₄) and concentrated. Purification via silica gel chromatography (0-50% EtOAc in hexanes) gave the title compound (20 mg, 23%). MS (ESI) mass calcd. for: C₁₆H₂₀F₃N₃O₃, 359.4; m/z found 260.1 [M-Boc]⁺.

Step B: (±)-(3-fluoro-2-(pyrimidin-2-yl)phenyl)(2-((5-(trifluoromethyl)pyrimidin-2-yl)oxy)-7-azabicyclo[2.2.1]heptan-7-yl)methanone: To (±)-tert-butyl 2-((5-(trifluoromethyl)pyrimidin-2-yl)oxy)-7-azabicyclo[2.2.1]heptane-7-carboxylate (20 mg, 0.06 mmol0 in DCM (2 mL) was added 2 mL (2M HCl in Et₂O) and stirred at rt for 3 h. The reaction mixture was concentrated and placed under high vacuum for 1 h. To the intermediate in DCM (2 mL) was added carboxylic acid (A-2) (13.3 mg, 0.06 mmol), HOBt (13.7 mg, 0.101 mmol), EDCI (19.4 mg, 0.101 mmol) and DIEPA (26 μL, 0.15 mmol). After stirring at rt for 2 h, saturated NaHCO₃ (aq.) was added and the mixture was extracted with DCM (3×). The combined organics were dried (Na₂SO₄), and concentrated. Purification via silica gel chromatography (0-100% EtOAc in hexanes) gave the title compound (9 mg, 38%). MS (ESI) mass calcd. for: C₂₂H₁₇F₄N₅O₂, 459.1; m/z found 460.1 [M+H]⁺. ¹H NMR (500 MHz, Chloroform-d) 8.88 (d, J=4.9 Hz, 1H), 8.81 (d, J=4.9 Hz, 1H), 8.74 (d, J=12.6 Hz, 2H), 7.63-7.27 (m, 3H), 7.14 (t, J=8.9 Hz, 1H), 4.99 (dt, J=8.3, 4.8 Hz, 1H), 4.87-4.66 (m, 1H), 4.16-3.97 (m, 1H), 2.07 (d, J=4.3 Hz, 1H), 1.91 (d, J=32.9 Hz, 1H), 1.85-1.68 (m, 2H), 1.66-1.60 (m, 1H), 1.51 (dd, J=7.9, 4.8 Hz, 1H).

Example 286 (±)-(3-fluoro-2-(pyrimidin-2-yl)phenyl)(2-((5-(trifluoromethyl)pyrimidin-2-yl)oxy)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Step A: (±)-tert-butyl 2-((5-(trifluoromethyl)pyrimidin-2-yl)oxy)-7-azabicyclo[2.2.1]heptane-7-carboxylate: To (±)-tert-butyl 2-hydroxy-7-azabicyclo[2.2.1]heptane-7-carboxylate (endo) (150 mg, 0.703 mol) in DMF (8 mL) was added 60 wt % NaH (56.3 mg, 1.41 mmol) in one portion. The reaction was heated at 80° C. for 5 min, then 2-chloro-5-(trifluoromethyl)pyrimidine (257 mg, 1.4 mmol) was added. After heating at 80° C. for 2 hours, water was added and the mixture extracted with DCM (3×). The combined organics were dried (Na₂SO₄) and concentrated. Purification via silica gel chromatography (0-50% EtOAc in hexanes) gave the title compound (130 mg, 51%). MS (ESI) mass calcd. for: C₁₆H₂₀F₃N₃O₃, 359.4; m/z found 260.1 [M-Boc]⁺. ¹H NMR (400 MHz, Chloroform-d) 8.82-8.71 (m, 2H), 5.28 (d, J=10.0 Hz, 1H), 4.59 (s, 1H), 4.25 (s, 1H), 2.43 (dddd, J=13.1, 10.1, 5.2, 2.8 Hz, 1H), 2.18-2.04 (m, 1H), 1.85 (dd, J=7.8, 3.8 Hz, 1H), 1.69 (s, 1H), 1.59 (s, 2H), 1.47 (s, 9H).

Step B: (3-fluoro-2-(pyrimidin-2-yl)phenyl)((1R,2S,4S)-2-((5-(trifluoromethyl)pyrimidin-2-yl)oxy)-7-azabicyclo[2.2.1]heptan-7-yl)methanone: To (±)-tert-butyl 2-((5-(trifluoromethyl)pyrimidin-2-yl)oxy)-7-azabicyclo[2.2.1]heptane-7-carboxylate (143 mg, 0.398 mmol) in DCM (3 mL) was added 2M HCl in Et₂O (3 mL). After 3 h at rt the reaction mixture was concentrated and placed under high vacuum for 1 h. To the intermediate in DCM (3 mL) was added carboxylic acid (A-2) (95.5 mg, 0.438 mmol), HOBt (88.9 mg, 0.658 mmol0, EDCI (126.1 mg, 0.658 mmol) and DIEPA (170 μL, 0.987 mmol). After stirring at rt for 2 h, saturated NaHCO₃ (aq.) was added and the mixture was extracted with DCM (3×). The combined organics were dried (Na₂SO₄), and concentrated. Purification via silica gel chromatography (0-100% EtOAc in hexanes) gave the title compound (78.6 mg, 47%). MS (ESI) mass calcd. for: C₂₂H₁₇F₄N₅O₂, 459.1; m/z found 460.1 [M+H]⁺. ¹H NMR (400 MHz, Chloroform-d) δ 8.85 (t, J=5.2 Hz, 2H), 8.76 (d, J=12.3 Hz, 2H), 7.47 (dd, J=8.5, 5.4 Hz, 1H), 7.29 (td, J=5.4, 4.9, 4.3 Hz, 3H), 5.58-5.40 (m, 1H), 5.30 (s, 1H), 5.09-4.92 (m, 1H), 4.67 (s, 1H), 4.34 (s, 1H), 4.02 (s, 1H), 2.61-2.39 (m, 1H), 2.32-2.08 (m, 1H), 1.90 (d, J=13.7 Hz, 1H).

Example 287 (3-ethoxy-6-methylpyridin-2-yl)((1S,2R,4R)-2-((5-(trifluoromethyl)pyrazin-2-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 238 substituting intermediate A-2 with intermediate A-8. MS (ESI) mass calcd. for: C₂₀H₂₂F₃N₅O₂, 421.2; m/z found 422.2 [M+H]⁺. ¹H NMR (400 MHz, Chloroform-d) 8.31 (s, 0.2H), 8.24 (s, 0.8H), 8.01-7.81 (m, 1.8H), 7.25-7.09 (m, 2H), 6.15 (d, J=8.0 Hz, 0.2H), 5.01-4.93 (m, 0.8H), 4.87-4.80 (m, 0.2H), 4.32-4.24 (m, 0.2H), 4.18-4.02 (m, 2.8H), 3.95 (d, J=4.6 Hz, 0.8H), 3.88-3.82 (m, 0.2H), 2.55-2.46 (m, 3H), 2.26-1.23 (m, 9H).

Example 288 (3-(2H-1,2,3-triazol-2-yl)pyridin-2-yl)((1S,2R,4R)-2-((5-(trifluoromethyl)pyrazin-2-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 238 substituting intermediate A-2 with intermediate A-27. MS (ESI) mass calcd. for: C₁₉H₁₇F₃N₈O, 430.1; m/z found 431.2 [M+H]⁺. ¹H NMR (400 MHz, Chloroform-d) 8.65 (dd, J=4.7, 1.5 Hz, 0.2H), 8.55 (dd, J=4.8, 1.5 Hz, 0.8H), 8.39-8.32 (m, 0.4H), 8.29-8.18 (m, 1.6H), 7.97-7.86 (m, 2.2H), 7.70 (s, 0.8H), 7.56 (dd, J=8.3, 4.7 Hz, 0.2H), 7.50 (dd, J=8.3, 4.7 Hz, 0.8H), 7.15 (d, J=8.6 Hz, 0.8H), 6.12 (d, J=8.6 Hz, 0.2H), 4.97-4.89 (m, 0.8H), 4.82 (d, J=5.2 Hz, 0.2H), 4.29 (td, J=7.9, 2.8 Hz, 1H), 4.12-4.07 (m, 0.2H), 4.04 (d, J=5.0 Hz, 0.8H), 2.27-1.43 (m, 6H).

Example 289 (2-methoxy-6-(pyrimidin-2-yl)phenyl)((1S,2R,4R)-2-((5-(trifluoromethyl)pyrazin-2-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 238 substituting intermediate A-2 with intermediate A-28. MS (ESI) mass calcd. for: C₂₃H₂₁F₃N₆O₂, 470.2; m/z found 471.2[M+H]⁺. ¹H NMR (400 MHz, Chloroform-d) 8.89-8.71 (m, 2H), 8.53-8.14 (m, 1.5H), 7.99-7.76 (m, 0.5H), 7.60-7.29 (m, 3.7H), 7.23-6.99 (m, 1H), 6.08 (d, J=8.9 Hz, 0.2H), 5.78 (d, J=8.5 Hz, 0.1H), 5.00-4.78 (m, 1H), 4.46-4.35 (m, 1H), 4.07 (s, 0.5H), 3.91-3.79 (m, 3.5H), 2.32-1.24 (m, 6H).

Example 290 (2-fluoro-6-(pyrimidin-2-yl)phenyl)((1S,2R,4R)-2-((5-(trifluoromethyl)pyrazin-2-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 238 substituting intermediate A-2 with intermediate A-6. MS (ESI) mass calcd. for: C₂₂H₁₈F₄N₆O, 458.1; m/z found 459.2 [M+H]⁺. ¹H NMR (400 MHz, Chloroform-d) 8.89-8.72 (m, 2H), 8.38-8.16 (m, 2H), 7.78 (dd, J=7.8, 1.1 Hz, 1H), 7.55-7.44 (m, 1H), 7.43-7.35 (m, 1H), 7.34-7.14 (m, 2H), 4.93-4.85 (m, 1H), 4.50-4.39 (m, 1H), 3.98-3.88 (m, 1H), 2.31-1.11 (m, 6H).

Example 291 (7-ethoxyquinolin-8-yl)((1S,2R,4R)-2-((5-(trifluoromethyl)pyrazin-2-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 238 substituting intermediate A-2 with intermediate A-29. MS (ESI) mass calcd. for: C₂₃H₂₂F₃N₅O₂, 457.2 m/z found 458.2 [M+H]⁺.

Example 292 (2-(1,4-dimethyl-1H-pyrazol-5-yl)-6-methoxyphenyl)((1 S,2R,4R)-2-((5-(trifluoromethyl)pyrazin-2-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 238 substituting intermediate A-2 with intermediate A-30. MS (ESI) mass calcd. for: C₂₄H₂₅F₃N₆O₂, 486.2 m/z found 487.2 [M+H]⁺.

Example 293 (3-methyl-2-(pyridin-2-yl)phenyl)((1S,2R,4R)-2-((5-(trifluoromethyl)pyrimidin-2-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 284 substituting title compound of Example 277 with title compound of Example 276 and 2-(tributylstannyl)oxazole with 2-(tributylstannyl)pyridine. MS (ESI) mass calcd. for: C₂₄H₂₂F₃N₅O, 453.2 m/z found 454.2 [M+H]⁺. ¹H NMR (400 MHz, Chloroform-d) 8.72-8.66 (m, 1H), 8.45 (s, 0.5H), 8.39 (s, 1.5H), 7.86-7.75 (m, 1H), 7.52-7.44 (m, 1H), 7.38-7.20 (m, 4.2H), 7.18-7.12 (m, 0.8H), 4.72-4.65 (m, 0.8H), 4.49-4.45 (m, 0.2H), 4.32 (s, 0.8H), 4.03-3.95 (m, 1H), 3.88-3.83 (m, 0.2H), 2.26 (s, 2.2H), 2.23 (s, 0.8H), 2.16 (dd, J=12.8, 7.9 Hz, 0.8H), 1.98-1.08 (m, 5.2H).

Example 294 (3-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl)((1S,2R,4R)-2-((5-(trifluoromethyl)pyridin-2-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 279 substituting intermediate A-2 with intermediate A-16. MS (ESI) mass calcd. for: C₂₁H₁₈F₄N₆O, 446.1 m/z found 447.2 [M+H]⁺. ¹H NMR (500 MHz, Chloroform-d) 8.33 (s, 0.2H), 8.23 (s, 0.8H), 7.96 (s, 1.55H), 7.91 (s, 0.45H), 7.57-7.48 (m, 0.4H), 7.44-7.29 (m, 2H), 7.30-7.21 (m, 1H), 7.21-7.13 (m, 0.8H), 6.72 (s, 0.6H), 6.36-6.25 (m, 1H), 5.34 (s, 0.2H), 4.78-4.69 (m, 0.8H), 4.61 (d, J=5.2 Hz, 0.2H), 4.28 (s, 0.8H), 4.12 (s, 0.2H), 4.05-3.95 (m, 1H), 2.17-1.41 (m, 6H).

Example 295 (3-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl)((1S,2R,4R)-2-((5-(trifluoromethyl)pyridin-2-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 279 substituting intermediate A-2 with intermediate A-24. MS (ESI) mass calcd. for: C₂₂H₂₁F₃N₆O, 442.1 m/z found 443.2 [M+H]⁺. ¹H NMR (500 MHz, Chloroform-d) 8.32 (s, 0.2H), 8.23 (s, 0.8H), 7.90 (s, 1.55H), 7.85 (s, 0.45H), 7.57-7.25 (m, 3.2H), 7.24-7.15 (m, 0.8H), 6.93 (s, 0.8H), 6.38-6.27 (m, 1H), 5.22 (s, 0.2H), 4.74-4.65 (m, 0.8H), 4.55 (d, J=4.7 Hz, 0.2H), 4.28 (s, 0.8H), 4.09 (s, 0.2H), 4.03-3.95 (m, 1H), 2.20 (s, 3H), 2.13-1.38 (m, 6H).

Example 296 (3-methyl-2-(oxazol-2-yl)phenyl)((1S,2R,4R)-2-((5-(trifluoromethyl)pyridin-2-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 279 substituting intermediate A-2 with intermediate A-31. MS (ESI) mass calcd. for: C₂₃H₂₁F₃N₄O₂, 442.2 m/z found 443.2 [M+H]⁺. ¹H NMR (500 MHz, Chloroform-d) 8.19 (s, 1H), 7.91-7.80 (m, 2H), 7.32-7.21 (m, 4H), 7.19-7.13 (m, 1H), 6.32 (d, J=8.8 Hz, 1H), 4.79-4.72 (m, 1H), 4.36-4.28 (m, 1H), 3.93 (d, J=4.6 Hz, 1H), 2.29 (s, 3H), 2.10 (dd, J=12.9, 8.1 Hz, 1H), 2.00-1.85 (m, 2H), 1.76-1.64 (m, 2H), 1.55-1.46 (m, 1H).

Example 297 (3-fluoro-2-(pyrimidin-2-yl)phenyl)((1R,2S,4S)-2-((5-(trifluoromethyl)pyrazin-2-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Prepared analogous to Example 238 substituting intermediate B-5 with intermediate B-8. MS (ESI) mass calcd. for C₂₂H₁₈F₄N₆O, 458.2; m/z found 459.1 [M+H]⁺. ¹H NMR (500 MHz, Chloroform-d) 8.91-8.84 (m, 2H), 8.27 (s, 1H), 8.19 (s, 1H), 7.65 (d, J=1.4 Hz, 1H), 7.44-7.34 (m, 2H), 7.24-7.16 (m, 2H), 4.77-4.68 (m, 1H), 4.43-4.33 (m, 1H), 4.07 (d, J=5.1 Hz, 1H), 2.16 (dd, J=13.0, 8.2 Hz, 1H), 2.10-1.99 (m, 1H), 1.98-1.86 (m, 1H), 1.78-1.65 (m, 2H), 1.58-1.48 (m, 1H).

Example 298: (3-fluoro-2-(oxazol-2-yl)phenyl)((1S,2R,4R)-2-((5-(trifluoromethyl)pyridin-2-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Example 299: (3-methyl-2-(pyrimidin-2-yl)phenyl)((1S,2R,4R)-2-((5-(trifluoromethyl)pyridin-2-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Example 300: (3-chloro-2-(pyrimidin-2-yl)phenyl)((1S,2R,4R)-2-((5-(trifluoromethyl)pyrazin-2-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Example 301: ((1S,2R,4R)-2-((5-bromopyridin-2-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)(3-fluoro-2-(oxazol-2-yl)phenyl)methanone

Example 302: ((1S,2R,4R)-2-((5-bromopyridin-2-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)(3-methyl-2-(oxazol-2-yl)phenyl)methanone

Example 303: ((1S,2R,4R)-2-((5-bromopyridin-2-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)(3-fluoro-2-(pyrimidin-2-yl)phenyl)methanone

Example 304: ((1S,2R,4R)-2-((5-bromopyridin-2-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)(3-methyl-2-(pyrimidin-2-yl)phenyl)methanone

Example 305: ((1S,2R,4R)-2-((5-bromopyridin-2-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)(3-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone

Example 306: ((1S,2R,4R)-2-((5-bromopyridin-2-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)(3-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone

Example 307: ((1S,2R,4R)-2-((5-bromopyrazin-2-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)(3-fluoro-2-(oxazol-2-yl)phenyl)methanone

Example 308: ((1S,2R,4R)-2-((5-bromopyrazin-2-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)(3-methyl-2-(oxazol-2-yl)phenyl)methanone

Example 309: ((1S,2R,4R)-2-((5-bromopyrazin-2-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)(3-fluoro-2-(pyrimidin-2-yl)phenyl)methanone

Example 310: ((1S,2R,4R)-2-((5-bromopyrazin-2-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)(3-methyl-2-(pyrimidin-2-yl)phenyl)methanone

Example 311: ((1S,2R,4R)-2-((5-bromopyrazin-2-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)(3-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone

Example 312: ((1S,2R,4R)-2-((5-bromopyrimidin-2-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)(3-fluoro-2-(oxazol-2-yl)phenyl)methanone

Example 313: ((1S,2R,4R)-2-((5-bromopyrimidin-2-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)(3-fluoro-2-(oxazol-2-yl)phenyl)methanone

Example 314: ((1S,2R,4R)-2-((5-bromopyrimidin-2-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)(3-methyl-2-(oxazol-2-yl)phenyl)methanone

Example 315: ((1S,2R,4R)-2-((5-bromopyrimidin-2-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)(3-fluoro-2-(pyrimidin-2-yl)phenyl)methanone

Example 316: ((1S,2R,4R)-2-((5-bromopyrimidin-2-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)(3-methyl-2-(pyrimidin-2-yl)phenyl)methanone

Example 317: ((1S,2R,4R)-2-((5-bromopyrimidin-2-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)(3-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone

Example 318: ((1S,2R,4R)-2-((5-bromopyrimidin-2-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)(3-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone

Example 319: (3-methyl-2-(pyridin-2-yl)phenyl)((1S,2R,4R)-2-((5-(trifluoromethyl)pyridin-2-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Example 320: (3-fluoro-2-(pyridin-2-yl)phenyl)((1S,2R,4R)-2-((5-(trifluoromethyl)pyridin-2-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Example 321: (3-fluoro-2-(pyridin-2-yl)phenyl)((1S,2R,4R)-2-((5-(trifluoromethyl)pyrimidin-2-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Example 322: (3-methyl-2-(pyridin-2-yl)phenyl)((1S,2R,4R)-2-((5-(trifluoromethyl)pyrazin-2-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Example 323: (3-fluoro-2-(pyridin-2-yl)phenyl)((2S)-2-((5-(trifluoromethyl)pyrazin-2-yl)amino)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Example 324: (3-fluoro-2-(pyrimidin-2-yl)phenyl)((1S,2R,4R)-2-((5-(trifluoromethyl)pyridin-2-yl)oxy)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Example 325: (2-methoxy-6-(pyrimidin-2-yl)phenyl)((1S,2R,4R)-2-((5-(trifluoromethyl)pyridin-2-yl)oxy)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Example 326: (5-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl)((1S,2R,4R)-2-((5-(trifluoromethyl)pyridin-2-yl)oxy)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Example 327: (4-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl)((1 S,2R,4R)-2-((5-(trifluoromethyl)pyridin-2-yl)oxy)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Example 328: (3-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl)((1S,2R,4R)-2-((5-(trifluoromethyl)pyridin-2-yl)oxy)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Example 329: (5-fluoro-2-(pyrimidin-2-yl)phenyl)((1S,2R,4R)-2-((5-(trifluoromethyl)pyridin-2-yl)oxy)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Example 330: (2-fluoro-6-(pyrimidin-2-yl)phenyl)((1S,2R,4R)-2-((5-(trifluoromethyl)pyridin-2-yl)oxy)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Example 331: (2-(2H-1,2,3-triazol-2-yl)phenyl)((1S,2R,4R)-2-((5-(trifluoromethyl)pyridin-2-yl)oxy)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Example 332: (6-methyl-3-(2H-1,2,3-triazol-2-yl)pyridin-2-yl)((1S,2R,4R)-2-((5-(trifluoromethyl)pyridin-2-yl)oxy)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Example 333: (3-methyl-2-(oxazol-2-yl)phenyl)((1S,2R,4R)-2-((5-(trifluoromethyl)pyridin-2-yl)oxy)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Example 334: (3-methyl-2-(pyridin-2-yl)phenyl)((1S,2R,4R)-2-((5-(trifluoromethyl)pyridin-2-yl)oxy)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Example 335: (2-(5-fluoropyrimidin-2-yl)phenyl)((1S,2R,4R)-2-((5-(trifluoromethyl)pyridin-2-yl)oxy)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Example 336: (2-fluoro-6-(2H-1,2,3-triazol-2-yl)phenyl)((1S,2R,4R)-2-((5-(trifluoromethyl)pyridin-2-yl)oxy)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Example 337: (5-methyl-3-(2H-1,2,3-triazol-2-yl)pyridin-2-yl)((1 S,2R,4R)-2-((5-(trifluoromethyl)pyridin-2-yl)oxy)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Example 338: (2-bromo-3-fluorophenyl)((1S,2R,4R)-2-((5-(trifluoromethyl)pyridin-2-yl)oxy)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Example 339: (3-fluoro-2-(pyrimidin-2-yl)phenyl)((1S,2R,4R)-2-((5-(trifluoromethyl)pyrazin-2-yl)oxy)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Example 340: (2-methoxy-6-(pyrimidin-2-yl)phenyl)((1S,2R,4R)-2-((5-(trifluoromethyl)pyrazin-2-yl)oxy)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Example 341: (5-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl)((1S,2R,4R)-2-((5-(trifluoromethyl)pyrazin-2-yl)oxy)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Example 342: (4-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl)((1S,2R,4R)-2-((5-(trifluoromethyl)pyrazin-2-yl)oxy)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Example 343: (3-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl)((1S,2R,4R)-2-((5-(trifluoromethyl)pyrazin-2-yl)oxy)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Example 344: (5-fluoro-2-(pyrimidin-2-yl)phenyl)((1S,2R,4R)-2-((5-(trifluoromethyl)pyrazin-2-yl)oxy)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Example 345: (2-fluoro-6-(pyrimidin-2-yl)phenyl)((1S,2R,4R)-2-((5-(trifluoromethyl)pyrazin-2-yl)oxy)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Example 346: (2-(2H-1,2,3-triazol-2-yl)phenyl)((1S,2R,4R)-2-((5-(trifluoromethyl)pyrazin-2-yl)oxy)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Example 347: (6-methyl-3-(2H-1,2,3-triazol-2-yl)pyridin-2-yl)((1S,2R,4R)-2-((5-(trifluoromethyl)pyrazin-2-yl)oxy)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Example 348: (3-methyl-2-(oxazol-2-yl)phenyl)((1S,2R,4R)-2-((5-(trifluoromethyl)pyrazin-2-yl)oxy)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Example 349: (3-methyl-2-(pyridin-2-yl)phenyl)((1S,2R,4R)-2-((5-(trifluoromethyl)pyrazin-2-yl)oxy)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Example 350: (2-(5-fluoropyrimidin-2-yl)phenyl)((1S,2R,4R)-2-((5-(trifluoromethyl)pyrazin-2-yl)oxy)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Example 351: (2-fluoro-6-(2H-1,2,3-triazol-2-yl)phenyl)((1S,2R,4R)-2-((5-(trifluoromethyl)pyrazin-2-yl)oxy)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Example 352: (5-methyl-3-(2H-1,2,3-triazol-2-yl)pyridin-2-yl)((1S,2R,4R)-2-((5-(trifluoromethyl)pyrazin-2-yl)oxy)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Example 353: (2-bromo-3-fluorophenyl)((1S,2R,4R)-2-((5-(trifluoromethyl)pyrazin-2-yl)oxy)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Example 354: (2-methoxy-6-(pyrimidin-2-yl)phenyl)((1 S,2R,4R)-2-((5-(trifluoromethyl)pyrimidin-2-yl)oxy)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Example 355: (5-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl)((1S,2R,4R)-2-((5-(trifluoromethyl)pyrimidin-2-yl)oxy)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Example 356: (4-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl)((1S,2R,4R)-2-((5-(trifluoromethyl)pyrimidin-2-yl)oxy)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Example 357: (3-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl)((1S,2R,4R)-2-((5-(trifluoromethyl)pyrimidin-2-yl)oxy)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Example 358: (5-fluoro-2-(pyrimidin-2-yl)phenyl)((1S,2R,4R)-2-((5-(trifluoromethyl)pyrimidin-2-yl)oxy)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Example 359: (2-fluoro-6-(pyrimidin-2-yl)phenyl)((1S,2R,4R)-2-((5-(trifluoromethyl)pyrimidin-2-yl)oxy)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Example 360: (2-(2H-1,2,3-triazol-2-yl)phenyl)((1S,2R,4R)-2-((5-(trifluoromethyl)pyrimidin-2-yl)oxy)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Example 361: (6-methyl-3-(2H-1,2,3-triazol-2-yl)pyridin-2-yl)((1S,2R,4R)-2-((5-(trifluoromethyl)pyrimidin-2-yl)oxy)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Example 362: (3-methyl-2-(oxazol-2-yl)phenyl)((1S,2R,4R)-2-((5-(trifluoromethyl)pyrimidin-2-yl)oxy)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Example 363: (3-methyl-2-(pyridin-2-yl)phenyl)((1S,2R,4R)-2-((5-(trifluoromethyl)pyrimidin-2-yl)oxy)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Example 364: (2-(5-fluoropyrimidin-2-yl)phenyl)((1S,2R,4R)-2-((5-(trifluoromethyl)pyrimidin-2-yl)oxy)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Example 365: (2-fluoro-6-(2H-1,2,3-triazol-2-yl)phenyl)((1S,2R,4R)-2-((5-(trifluoromethyl)pyrimidin-2-yl)oxy)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Example 366: (5-methyl-3-(2H-1,2,3-triazol-2-yl)pyridin-2-yl)((1S,2R,4R)-2-((5-(trifluoromethyl)pyrimidin-2-yl)oxy)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Example 367: (2-bromo-3-fluorophenyl)((1S,2R,4R)-2-((5-(trifluoromethyl)pyrimidin-2-yl)oxy)-7-azabicyclo[2.2.1]heptan-7-yl)methanone

Assays

The in vitro affinity of the compounds of the invention for the rat/human orexin 1 and human orexin 2 receptors was determined by competitive radioligand binding using [3H] (1-(5-(2-fluoro-phenyl)-2-methyl-thiazol-4-yl)-1-((S)-2-(5-phenyl-(1,3,4)oxadiazol-2-ylmethyl)-pyrrolidin-1-yl)-methanone)(Langmead et al., 2004) and [3H]EMPA (n-ethyl-2[96-methoxy-pyridin-3-yl)-(toluene-2-sulfonyl)-amino]-N-pyridin-3-ylmethyl acetamide), respectively (Langmead et al., 2004, British Journal of Pharmacology 141:340-346; Malherbe et al., 2004, British Journal of Pharmacology 156:1326-41).

The in vitro functional antagonism of the compounds on the human orexin 1 and orexin 2 receptors was determined using fluorometric imaging plate reader (FLIPR) based calcium assays.

Rat and Human Orexin 1 Receptor Radioligand Binding Studies

Human Embryonic Kidney 293 cells (HEK293) stably expressing rat orexin 1 receptor (Genebank accession number NM_001525) or Chinese ovary cells (CHO) stably expressing human orexin 1 receptor (Genebank accession number NM_001526) were grown to confluency in DMEM (Hyclone, cat # SH30022), 10% FBS, 1× Pen/Strep, 1× sodium pyruvate, 10 mM HEPES, 600 μg/mL G418 and DMEM/F₁₂ (Gibco, Cat #11039), 10% FBS, 1× Pen/Strep, 600 μg/mL G418 media, respectively on 150 cm2 tissue culture plates, washed with 5 mM EDTA in PBS (HyClone Dulbecco's Phosphate Buffered Saline 1× with Calcium and Magnesium, Cat # SH30264.01, hereafter referred to simply as PBS) and scraped into 50 ml tubes. After centrifugation (2K×G, 5 min at 4° C.), the supernatant was aspirated and the pellets frozen and stored at −800 C. Cells were resuspended in PBS in the presence of 1 tablet of protease inhibitor cocktail (Roche, Cat. #11836145001) per 50 mL. Each cell pellet from a 15 cm plate was resuspended in 10 mL, stored on ice, and homogenized for 45 sec prior to addition to the reactions. Competition binding experiments in 96 well polypropylene plates were performed using [3H]-SB674042 (Moraveck Corporation, specific activity=35.3 Ci/mmol), diluted to a 10 nM concentration in PBS (4 nM final). Compounds were solubilized in 100% DMSO (Acros Organics, Cat. #61042-1000) and tested over a range of 7 concentrations (from 0.1 nM to 10 μM). The final concentration of DMSO in the reactions is equal to or less than 0.1%. Total and nonspecific binding was determined in the absence and presence of 10 μM almorexant. The total volume of each reaction is 200 μL (20 μL of diluted compounds, 80 μL of [³H]-(1-(5-(2-fluoro-phenyl)-2-methyl-thiazol-4-yl)-1-((S)-2-(5-phenyl-(1,3,4)oxadiazol-2-ylmethyl)-pyrrolidin-1-yl)-methanone) diluted in PBS and 100 μL of the cell suspension). Reactions were run for 60 min at room temperature and terminated by filtration through GF/C filter plates (PerkinElmer, Cat. #6005174) presoaked in 0.3% polyethylenimine using the cell harvester (PerkinElmer Filtermate). The plates were washed 3 times by aspirating 30 ml PBS through the plates. Plates were dried in 55° C. oven for 60 min, scintillation fluid was added, and the radioactivity was counted on a Topcount (Packard).

IC₅₀ values (i.e. concentration of unlabelled compound required to compete for 50% of specific binding to the radioligand) was calculated using the GraphPad Prism software (GraphPad Prism Software Inc., San Diego, Calif.) with a fit to a sigmoidal dose-response curve. Apparent Ki values were calculated as Ki=IC₅₀/(1+C/Kd), where C is concentration of radioligand and Kd=4 nM for rat orexin 1 receptor and 6 nM for human orexin 1 receptor.

Human Orexin 2 Receptor Radioligand Binding Studies

HEK293 stably expressing human orexin 2 receptor (Genebank accession number NM_001526) were grown to confluency in DMEM (Hyclone, cat # SH30022), 10% FBS, 1× Pen/Strep, 1× NaPyruvate, 10 mM HEPES, 600 g/ml G418 media on 150 cm² tissue culture plates, washed with 5 mM EDTA in PBS (HyClone Dulbecco's Phosphate Buffered Saline 1× with Calcium and Magnesium, Cat # SH30264.01, hereafter referred to simply as PBS) and scraped into 50 ml tubes. After centrifugation (2K xG, 5 min at 40° C.), the supernatant was aspirated and the pellets frozen and stored at −800° C. Cells were resuspended in PBS in the presence of 1 tablet of protease inhibitor cocktail (Roche, Cat. #11836145001) per 50 mL. Each cell pellet from a 15 cm plate was resuspended in 10 mL, stored on ice, and homogenized for 45 sec just prior to addition to the reactions. Competition binding experiments in 96 well polypropylene plates were performed using [3H]-EMPA (Moraveck Corporation, specific activity=29.6 Ci/mmol), diluted to a 5 nM concentration in PBS (2 nM final concentration). Compounds were solubilized in 100% DMSO (Acros Organics, Cat. #61042-1000) and tested over a range of 7 concentration (from 0.1 nM to 10 μM). The final concentration of DMSO in the reactions is equal to or less than 0.1%. Total and nonspecific binding was determined in the absence and presence of 10 μM almorexant. The total volume of each reaction is 200 μL (20 μL of diluted compounds, 80 μL of [3H]-EMPA diluted in PBS and 100 μL of the cell suspension). Reactions were run for 60 min at room temperature and terminated by filtration through GF/C filter plates (PerkinElmer, Cat. #6005174) presoaked in 0.3% polyethylenimine using the cell harvester (PerkinElmer Filtermate). The plates were washed 3 times by aspirating 30 ml PBS through the plates. Plates were dried in 55° C. oven for 60 min, scintillation fluid was added, and the radioactivity was counted on a Topcount (Packard).

IC₅₀ values (i.e. concentration of unlabelled compound required to compete for 50% of specific binding to the radioligand) was calculated using the GraphPad Prism software (GraphPad Prism Software Inc., San Diego, Calif.) with a fit to a sigmoidal dose-response curve. Apparent Ki values were calculated as Ki=IC₅₀/(1+C/Kd), where C is concentration of radioligand and Kd=2 nM.

Human Orexin 1 Receptor Ca2+ Mobilization Assay

CHO cells stably transfected with the human orexin 1 receptor (Genebank accession number NM_001526) were grown to confluency in DMEM/F12, 10% FBS, 1× pen-strep, 400 g/ml G418. Cells were seeded on to 384-well Packard viewplates at a density of 10,000 cells/well and incubated overnight at 370 C, 5% CO₂. The cells were dye-loaded with BD Calcium Assay kit (BD, cat #640178) in HBSS (Gibco, cat#14025-092) with 2.5 mM probenecid and incubated at 37° C., 5% CO2 for 45 min. Cells were pre-incubated with compounds (diluted in DMEM/F-12) for 15-30 minutes before agonist (orexin A, 10 nM) stimulation. Ligand-induced Ca²⁺ release was measured using a Fluorometric Imaging Plate Reader (FLIPR, Molecular Devices, Sunnyvale, Calif.). Functional responses were measured as peak fluorescence intensity minus basal. The concentration of agonist that produced a half-maximal response is represented by the EC₅₀ value. Antagonistic potency values were converted to apparent pKB values using a modified Cheng-Prusoff correction. Apparent pKB=−log IC₅₀/1+[conc agonist/EC₅₀]. Data are expressed as mean±S.E.M.

Human Orexin 2 Receptor Ca2+ Mobilization Assay

PFSK-1 cells endogenously expressing the human orexin 2 receptor were grown to confluency in RPMI1640 (Hyclone, cat#30027.02), 10% FBS, 1× pen-strep. Cells were seeded on to 384-well Packard viewplates at a density of 5,000 cells/well and incubated overnight at 370 C, 5% CO₂. The cells were dye-loaded with BD Calcium Assay kit (BD, cat #640178) in HBSS (Gibco, cat#14025-092) with 2.5 mM probenecid and incubated at 37° C., 5% CO2 for 45 min. Cells were pre-incubated with compounds (diluted in DMEM/F-12) for 15-30 minutes before agonist (orexin B, 100 nM) stimulation. Ligand-induced Ca²⁺ release was measured using a Fluorometric Imaging Plate Reader (FLIPR, Molecular Devices, Sunnyvale, Calif.). Functional responses were measured as peak fluorescence intensity minus basal. The concentration of agonist that produced a half-maximal response is represented by the EC₅₀ value. Antagonistic potency values were converted to apparent pKB values using a modified Cheng-Prusoff correction. Apparent pKB=−log IC₅₀/1+[conc agonist/EC50]. Data are expressed as mean±S.E.M.

Preferred compounds of the invention are set forth in the table below. Orexin receptor activity of certain compounds of the invention is also set forth in the below table.

rOX1 hOX1 hOX2 Ex. K_(i) K_(i) K_(i) Compound No. Compound (nm) (nm) (nm) Name  1

25 41 276 (5-fluoro-2- (pyrimidin-2- yl)phenyl)((1S,2R,4R)- 2-((pyridin-2- yloxy)methyl)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone  2

31 23 500 (±)-(6-methyl-3- (pyrimidin-2- yl)pyridin-2-yl)(2- ((pyridin-2- yloxy)methyl)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone  3A

24 19 268 (6-methyl-3- (pyrimidin-2- yl)pyridin-2- yl)((1S*,2R*,4R*)-2- ((pyridin-2- yloxy)methyl)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone  3B

>10000 >10000 (6-methyl-3- (pyrimidin-2- yl)pyridin-2- yl)((1R*,2S*,4S*)-2- ((pyridin-2- yloxy)methyl)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone  4

36 41 927 (±)-(6-methyl-3-(2H- 1,2,3-triazol-2- yl)pyridin-2-yl)(2- ((pyridin-2- yloxy)methyl)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone  5A

14 15 428 (6-methyl-3-(2H- 1,2,3-triazol-2- yl)pyridin-2- yl)((1S,2R,4R)-2- ((pyridin-2- yloxy)methyl)-7- azabicydo[2.2.1]heptan- 7-yl)methanone  5B

>10000 >10000 (6-methyl-3-(2H- 1,2,3-triazol-2- yl)pyridin-2- yl)((1R,2S,4S)-2- ((pyridin-2- yloxy)methyl)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone  6

14 15 428 (6-methyl-3-(2H- 1,2,3-triazol-2- yl)pyridin-2- yl)((1S,2R,4R)-2- ((pyridin-2- yloxy)methyl)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone  7

19 19 198 (±)-(2-(((5- fluoropyridin-2- yl)oxy)methyl)-7- azabicyclo[2.2.1]heptan- 7-yl)(6-methyl-3- (2H-1,2,3-triazol-2- yl)pyridin-2- yl)methanone  8A

9 14 94 ((1S,2R,4R)-2-(((5- fluoropyridin-2- yl)oxy)methyl)-7- azabicyclo[2.2.1]heptan- 7-yl)(6-methyl-3- (2H-1,2,3-triazol-2- yl)pyridin-2- yl)methanone  8B

>10000 >10000 ((1R,2S,4S)-2-(((5- fluoropyridin-2- yl)oxy)methyl)-7- azabicyclo[2.2.1]heptan- 7-yl)(6-methyl-3- (2H-1,2,3-triazol-2- yl)pyridin-2- yl)methanone  9

9 57 (±)-(2-(((5- fluoropyridin-2- yl)oxy)methyl)-7- azabicyclo[2.2.1]heptan- 7-yl)(5-methyl-2- (2H-1,2,3-triazol-2- yl)phenyl)methanone  10A

4 3 32 ((1S,2R,4R)-2-(((5- fluoropyridin-2- yl)oxy)methyl)-7- azabicyclo[2.2.1]heptan- 7-yl)(5-methyl-2- (2H-1,2,3-triazol-2- yl)phenyl)methanone  10B

3937 3200 5148 ((1R,2S,4S)-2-(((5- fluoropyridin-2- yl)oxy)methyl)-7- azabicyclo[2.2.1]heptan- 7-yl)(5-methyl-2- (2H-1,2,3-triazol-2- yl)phenyl)methanone  11

10 12 (±)-(2-(((5- fluoropyridin-2- yl)oxy)methyl)-7- azabicyclo[2.2.1]heptan- 7-yl)(2-(thiophen-2- yl)phenyl)methanone  12A

177 339 ((1S*,2R*,4R*)-2- (((5-fluoropyridin-2- yl)oxy)methyl)-7- azabicyclo[2.2.1]heptan- 7-yl)(2-(thiophen-2- yl)phenyl)methanone  12B

3 5 ((1R*,2S*,4S*)-2- (((5-fluoropyridin-2- yl)oxy)methyl)-7- azabicyclo[2.2.1]heptan- 7-yl)(2-(thiophen-2- yl)phenyl)methanone  13

118 109 (±)-(5-methyl-2-(2H- 1,2,3-triazol-2- yl)phenyl)(2-(((4- (trifluoromethyl)pyrimidin- 2-yl)oxy)methyl)- 7- azabicyclo[2.2.1]heptan- 7-yl)methanone  14

50 71 (±)-(5-methyl-2-(2H- 1,2,3-triazol-2- yl)phenyl)(2-(((5- (trifluoromethyl)pyridin- 2-yl)oxy)methyl)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone  15

56 120 (±)-(5-methyl-2-(2H- 1,2,3-triazol-2- yl)phenyl)(2-(((3- (trifluoromethyl)pyridin- 2-yl)oxy)methyl)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone  16

20 42 (±)-(5-methyl-2-(2H- 1,2,3-triazol-2- yl)phenyl)(2-(((6- (trifluoromethyl)pyridin- 2-yl)oxy)methyl)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone  17

41 69 (±)-(5-methyl-2-(2H- 1,2,3-triazol-2- yl)phenyl)(2-(((4- methylpyridin-2- yl)oxy)methyl)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone  18

12 44 (±)-(5-methyl-2-(2H- 1,2,3-triazol-2- yl)phenyl)(2-(((6- methylpyridin-2- yl)oxy)methyl)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone  19

12 44 (±)-(5-methyl-2-(2H- 1,2,3-triazol-2- yl)phenyl)(2-(((5- methylpyridin-2- yl)oxy)methyl)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone  20

270 364 (±)-(2-(((3,6- dimethylpyrazin-2- yl)oxy)methyl)-7- azabicyclo[2.2.1]heptan- 7-yl)(5-methyl-2- (2H-1,2,3-triazol-2- yl)phenyl)methanone  21

300 487 (±)-(5-methyl-2-(2H- 1,2,3-triazol-2- yl)phenyl)(2-(((3- (trifluoromethyl) quinoxalin-2- yl)oxy)methyl)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone  22

47 50 (±)-(2-(2H-1,2,3- triazol-2-yl)phenyl)(2- (((5-fluoropyridin-2- yl)oxy)methyl)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone  23

322 1500 (±)-2-(((5- fluoropyridin-2- yl)oxy)methyl)-7- azabicyclo[2.2.1]heptan- 7-yl)(quinolin-8- yl)methanone  24

122 164 (±)-2-(((5- fluoropyridin-2- yl)oxy)methyl)-7- azabicyclo[2.2.1]heptan- 7-yl)(naphthalen-1- yl)methanone  25

74 160 (±)-2-(((5- fluoropyridin-2- yl)oxy)methyl)-7- azabicyclo[2.2.1]heptan- 7-yl)(2- methylnaphthalen-1- yl)methanone  26

117 394 (±)-2-(1H-pyrazol-1- yl)phenyl)(2-(((5- fluoropyridin-2- yl)oxy)methyl)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone  27

677 380 (±)-2-(((5- fluoropyridin-2- yl)oxy)methyl)-7- azabicyclo[2.2.1]heptan- 7-yl)(3-phenylfuran- 2-yl)methanone  28

14 11 (±)-(2- ethoxynaphthalen-1- yl)(2-(((5- fluoropyridin-2- yl)oxy)methyl)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone  29

11 60 (±)-(5-(2- fluorophenyl)-2- methylthiazol-4-yl)(2- (((5-fluoropyridin-2- yl)oxy)methyl)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone  30

47 149 (±)-(5-fluoro-2-(2H- 1,2,3-triazol-2- yl)phenyl)(2-(((5- fluoropyridin-2- yl)oxy)methyl)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone  31

33 122 (±)-(2-fluoro-6- (pyrimidin-2- yl)phenyl)(2-(((5- fluoropyridin-2- yl)oxy)methyl)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone  32

21 123 (±)-(5-fluoro-2- (pyrimidin-2- yl)phenyl)(2-(((5- fluoropyridin-2- yl)oxy)methyl)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone  33

15 9 39 (±)-(2-(((5- fluoropyridin-2- yl)oxy)methyl)-7- azabicyclo[2.2.1]heptan- 7-yl)(5-methyl-2- (pyrimidin-2- yl)phenyl)methanone  34

60 467 (±)-(2-(2H-1,2,3- triazol-2-yl)phenyl)(2- ((quinoxalin-2- yloxy)methyl)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone  35

69 58 693 (±)-(2-fluoro-6-(2H- 1,2,3-triazol-2- yl)phenyl)(2- ((quinoxalin-2- yloxy)methyl)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone  36

70 107 (±)-(5-methyl-2-(2H- 1,2,3-triazol-2- yl)phenyl)(2- ((quinoxalin-2- yloxy)methyl)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone  37

300 487 (±)-(5-fluoro-2-(2H- 1,2,3-triazol-2- yl)phenyl)(2- ((quinoxalin-2- yloxy)methyl)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone  38

120 383 (±)-(5-methyl-2- (pyrimidin-2- yl)phenyl)(2- ((quinoxalin-2- yloxy)methyl)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone  39

29 27 (±)-(2-(((4,6- dimethylpyrimidin-2- yl)oxy)methyl)-7- azabicyclo[2.2.1]heptan- 7-yl)(5-methyl-2- (2H-1,2,3-triazol-2- yl)phenyl)methanone  40

5000 1203 (±)-2-(((4,6- dimethylpyrimidin-2- yl)oxy)methyl)-7- azabicyclo[2.2.1]heptan- 7-yl)(3-methyl-5- phenylisoxazol-4- yl)methanone  41

35 22 (±)-(2-(((4,6- dimethylpyrimidin-2- yl)oxy)methyl)-7- azabicyclo[2.2.1]heptan- 7-yl)(2- ethoxynaphthalen-1- yl)methanone  42

1277 253 (±)-(2-(((4,6- dimethylpyrimidin-2- yl)oxy)methyl)-7- azabicyclo[2.2.1]heptan- 7-yl)(2- ethoxyphenyl)methanone)  43

222 92 (±)-(2-(((4,6- dimethylpyrimidin-2- yl)oxy)methyl)-7- azabicyclo[2.2.1]heptan- 7-yl)(2-fluoro-6- (pyrimidin-2- yl)phenyl)methanone  44

400 104 (±)-(2-(((4,6- dimethylpyrimidin-2- yl)oxy)methyl)-7- azabicyclo[2.2.1]heptan- 7-yl)(5-fluoro-2- (pyrimidin-2- yl)phenyl)methanone  45

79 59 (±)-(2-(((4,6- dimethylpyrimidin-2- yl)oxy)methyl)-7- azabicyclo[2.2.1]heptan- 7-yl)(5-methyl-2- (pyrimidin-2- yl)phenyl)methanone  46

82 10 (±)-(2-(((4,6- dimethylpyrimidin-2- yl)oxy)methyl)-7- azabicyclo[2.2.1]heptan- 7-yl)(2-(thiophen-2- yl)phenyl)methanone  47

460 418 (±)-(6-methyl-2-(2H- 1,2,3-triazol-2- yl)pyridin-2-yl)(2- (((5- (trifluoromethyl)pyridin- 2-yl)oxy)methyl)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone  48

3900 4700 (±)-(3-ethoxy-6- methylpyridin-2-yl)(2- (((5- (trifluoromethyl)pyridin- 2-yl)oxy)methyl)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone  49

81 69 192 (±)-(2-(((5- bromopyridin-2- yl)oxy)methyl)-7- azabicyclo[2.2.1]heptan- 7-yl)(6-methyl-3- (2H-1,2,3-triazol-2- yl)pyridin-2- yl)methanone  50

460 4399 (±)-(2-(((5- bromopyridin-2- yl)oxy)methyl)-7- azabicyclo[2.2.1]heptan- 7-yl)(3-fluoro-2- methoxyphenyl)methanone  51

974 1800 (±)-(2-(((5- bromopyridin-2- yl)oxy)methyl)-7- azabicyclo[2.2.1]heptan- 7-yl)(3-ethoxy-6- methylpyridin-2- yl)methanone  52

350 2300 (±)-(3-fluoro-2- (pyrimidin-2- yl)phenyl)(2-((pyridin- 2-yloxy)methyl)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone  53

2200 >10000 (±)-(6-methyl-3-(2H- 1,2,3-triazol-2- yl)pyridin-2-yl)(2- ((pyridazin-3- yloxy)methyl)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone  54

3500 2200 (±)-(6-methyl-3-(2H- 1,2,3-triazol-2- yl)pyridin-2-yl)(2- (((2-methylpyridin-3- yl)oxy)methyl)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone  55

119 150 202 (±)-(6-methyl-3-(2H- 1,2,3-triazol-2- yl)pyridin-2-yl)(2- (((3-methylpyridin-2- yl)oxy)methyl)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone  56

>10000 >10000 (±)-(2-(((1-methyl-1H- pyrazol-5- yl)oxy)methyl)-7- azabicyclo[2.2.1]heptan- 7-yl)(6-methyl-3- (2H-1,2,3-triazol-2- yl)pyridin-2- yl)methanone  57

1000 7300 (±)-(6-methyl-3-(2H- 1,2,3-triazol-2- yl)pyridin-2-yl)(2- ((pyridin-4- yloxy)methyl)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone  58

88 117 2400 (±)-(6-methyl-3-(2H- 1,2,3-triazol-2- yl)pyridin-2-yl)(2- ((pyridin-3- yloxy)methyl)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone  59

2600 4900 (±)-(6-methyl-3-(2H- 1,2,3-triazol-2- yl)pyridin-2-yl)(2- ((pyrimidin-2- yloxy)methyl)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone  60

7800 >10000 (±)-(6-methyl-3-(2H- 1,2,3-triazol-2- yl)pyridin-2-yl)(2- ((pyrazin-2- yloxy)methyl)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone  61

2800 >10000 (±)-(6-methyl-3-(2H- 1,2,3-triazol-2- yl)pyridin-2-yl)(2- ((pyrimidin-4- yloxy)methyl)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone  62

74 46 188 (±)-(6-methyl-3-(2H- 1,2,3-triazol-2- yl)pyridin-2-yl)(2- (((6-methylpyridin-2- yl)oxy)methyl)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone  63

25 25 339 (±)-(2-(((5- fluoropyridin-2- yl)oxy)methyl)-7- azabicyclo[2.2.1]heptan- 7-yl)(6-methyl-3- (oxazol-2-yl)pyridin- 2-yl)methanone  64

18 24 81 (±)-(2-(((5- fluoropyridin-2- yl)oxy)methyl)-7- azabicyclo[2.2.1]heptan- 7-yl)(6-methyl-3- (pyrimidin-2- yl)pyridin-2- yl)methanone  65

1440 6200 (±)-(3,6′-dimethyl- [2,3′-bipyridin]-2′- yl)(2-(((5- fluoropyridin-2- yl)oxy)methyl)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone  66

197 293 620 (±)-(2-(((5- fluoropyridin-2- yl)oxy)methyl)-7- azabicyclo[2.2.1]heptan- 7-yl)(6-methyl-3-(3- methyl-1,2,4- oxadiazol-5- yl)pyridin-2- yl)methanone  67

48 69 258 (±)-(2-(((5- fluoropyridin-2- yl)oxy)methyl)-7- azabicyclo[2.2.1]heptan- 7-yl)(6-methyl-3-(3- methyl-1H-pyrazol-1- yl)pyridin-2- yl)methanone  68

27 22 576 (±)-(2-(((5- fluoropyridin-2- yl)oxy)methyl)-7- azabicyclo[2.2.1]heptan- 7-yl)(6-methyl-3- (pyrrolidin-1- yl)pyridin-2- yl)methanone  69

40 64 174 (±)-(2-(((5- fluoropyridin-2- yl)oxy)methyl)-7- azabicyclo[2.2.1]heptan- 7-yl)(6-methyl-3-(3- methylisoxazol-5- yl)pyridin-2- yl)methanone  70

88 62 624 (±)-(2-(((5- fluoropyridin-2- yl)oxy)methyl)-7- azabicyclo[2.2.1]heptan- 7-yl)(6-methyl-3- (1H-pyrazol-1- yl)pyridin-2- yl)methanone  71

1200 3700 (±)-(5-methyl-3-(2H- 1,2,3-triazol-2- yl)pyridin-2-yl)(2- ((pyridin-2- yloxy)methyl)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone  72

137 162 2400 (±)-(4-methyl-3-(2H- 1,2,3-triazol-2- yl)pyridin-2-yl)(2- ((pyridin-2- yloxy)methyl)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone  73

278 7900 (±)-(3- (dimethylamino)-6- methylpyridin-2-yl)(2- ((pyridin-2- yloxy)methyl)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone  74

359 1700 (±)-(3-(2H-1,2,3- triazol-2-yl)quinolin- 2-yl)(2-((pyridin-2- yloxy)methyl)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone  75

18 7 220 (±)-(7-ethoxyquinolin- 8-yl)(2-((pyridin-2- yloxy)methyl)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone  76

>10000 >10000 (±)-(3,6- dimethylimidazo[1,2- a]pyridin-5-yl)(2- ((pyridin-2- yloxy)methyl)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone  77

103 66 867 (±)-(1-methyl-4- phenyl-1H-pyrazol-3- yl)((1S,2R,4R)-2- ((pyridin-2- yloxy)methyl)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone  78

418 3100 (±)-(1-methyl-3- phenyl-1H-pyrazol-4- yl)((1S,2R,4R)-2- ((pyridin-2- yloxy)methyl)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone  79

2400 8500 (±)-((3,7- dimethylimidazo[1,2- a]pyridin-8-yl)(2- ((pyridin-2- yloxy)methyl)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone  80

1100 >10000 (±)-(7- methylimidazo[1,2- a]pyridin-8-yl)(2- ((pyridin-2- yloxy)methyl)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone  81

916 2900 (±)-(1-methyl-4- phenyl-1H-pyrazol-5- yl)(2-((pyridin-2- yloxy)methyl)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone  82

>10000 >10000 (±)-((6- methylimidazo[1,2- a]pyridin-5-yl)(2- ((pyridin-2- yloxy)methyl)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone  83

17 12 271 (±)-(3- ethoxyisoquinolin-4- yl)(2-((pyridin-2- yloxy)methyl)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone  84

2600 9701 (±)-(1-methyl-5- phenyl-1H-pyrazol-4- yl)(-2-((pyridin-2- yloxy)methyl)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone  85

>10000 >10000 (±)-(6-methyl-3-(4- methylpiperazin-1- yl)pyridin-2-yl)(2- ((pyridin-2- yloxy)methyl)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone  86

>10000 >10000 (±)-(6-methyl-3- (piperazin-1- yl)pyridin-2-yl)(2- ((pyridin-2- yloxy)methyl)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone  87

4200 >10000 (±)-(6-methyl-3- morpholinopyridin-2- yl)((1S,2R,4R)-2- ((pyridin-2- yloxy)methyl)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone  88

47 49 690 (±)-(7- methoxyquinolin-8- yl)(2-((pyridin-2- yloxy)methyl)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone  89

11 10 38 (±)-(2- ethoxynaphthalen-1- yl)(2-((pyridin-2- yloxy)methyl)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone  90

3000 >10000 (±)-(3,6′-dimethyl- [2,3′-bipyridin]-2′- yl)(2-((pyridin-2- yloxy)methyl)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone  91

624 3300 (±)-(3-(2H-1,2,3- triazol-2-yl)pyridin-2- yl)(2-((pyridin-2- yloxy)methyl)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone  92

20 11 218 (±)-(2-methyl-5- phenylthiazol-4-yl)(2- ((pyridin-2- yloxy)methyl)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone  93

40 73 836 (±)-(6-methyl-3- (oxazol-2-yl)pyridin- 2-yl)(2-((pyridin-2- yloxy)methyl)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone  94

170 200 2100 (±)-(6-methyl-3-(3- methylisoxazol-5- yl)pyridin-2-yl)(2- ((pyridin-2- yloxy)methyl)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone  95

247 3700 (±)-(6-methyl-3-(1H- pyrazol-1-yl)pyridin- 2-yl)(2-((pyridin-2- yloxy)methyl)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone  96

70 76 950 (±)-(6-methyl-3-(4- methyl-1H-pyrazol-1- yl)pyridin-2-yl)(2- ((pyridin-2- yloxy)methyl)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone  97

35 32 840 (±)-(6-methyl-3- (pyrrolidin-1- yl)pyridin-2-yl)(2- ((pyridin-2- yloxy)methyl)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone  98

>10000 >10000 (±)-(3,6′-dimethyl- [2,3′-bipyridin]-2′- yl)(2-(((5- fluoropyrimidin-2- yl)oxy)methyl)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone  99

1500 2900 (±)-(2-(((5- fluoropyrimidin-2- yl)oxy)methyl)-7- azabicyclo[2.2.1]heptan- 7-yl)(6-methyl-3-(3- methylisoxazol-5- yl)pyridin-2- yl)methanone 100

950 1800 (±)-(2-(((5- fluoropyrimidin-2- yl)oxy)methyl)-7- azabicyclo[2.2.1]heptan- 7-yl)(6-methyl-3- (oxazol-2-yl)pyridin- 2-yl)methanone 101

650 1200 (±)-(2-(((5- fluoropyrimidin-2- yl)oxy)methyl)-7- azabicyclo[2.2.1]heptan- 7-yl)(6-methyl-3- (pyrrolidin-1- yl)pyridin-2- yl)methanone 102

(±)-(2-(((5- fluoropyrimidin-2- yl)oxy)methyl)-7- azabicyclo[2.2.1]heptan- 7-yl)(6-methyl-3- (pyrimidin-2- yl)pyridin-2- yl)methanone 103

1700 3600 (±)-(2-(((5- fluoropyrimidin-2- yl)oxy)methyl)-7- azabicyclo[2.2.1]heptan- 7-yl)(6-methyl-3-(4- methyl-1H-pyrazol-1- yl)pyridin-2- yl)methanone 104

1100 4600 (±)-(2-(((5- fluoropyrimidin-2- yl)oxy)methyl)-7- azabicyclo[2.2.1]heptan- 7-yl)(6-methyl-3- (1H-pyrazol-1- yl)pyridin-2- yl)methanone 105

(±)-(2-(((5- fluoropyridin-2- yl)oxy)methyl)-7- azabicyclo[2.2.1]heptan- 7-yl)(5-methyl-2- (2H-1,2,3-triazol-2- yl)phenyl)methanone 106

300 154 (±)-(2,6- dimethoxyphenyl)(2- (((5-fluoropyridin-2- yl)oxy)methyl)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone 107

440 2200 (±)-((3-fluoro-2- methoxyphenyl)(2- (((5-fluoropyridin-2- yl)oxy)methyl)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone 108

10 12 12 (±)-(2-(((5- fluoropyridin-2- yl)oxy)methyl)-7- azabicyclo[2.2.1]heptan- 7-yl)(2-methoxy-6- (2H-1,2,3-triazol-2- yl)phenyl)methanone 109

29 20 99 (±)-(5-fluoro-2-(1H- pyrazol-5- yl)phenyl)(2-(((5- fluoropyridin-2- yl)oxy)methyl)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone 110

54 67 94 (±)-(2-(((5- fluoropyridin-2- yl)oxy)methyl)-7- azabicyclo[2.2.1]heptan- 7-yl)(2-methyl-6- (2H-1,2,3-triazol-2- yl)phenyl)methanone 111

19 19 198 (±)-(2-(((5- fluoropyridin-2- yl)oxy)methyl)-7- azabicyclo[2.2.1]heptan- 7-yl)(6-methyl-3- (2H-1,2,3-triazol-2- yl)pyridin-2- yl)methanone 112

480 1000 (±)-(5-chloro-3-(2H- 1,2,3-triazol-2- yl)pyridin-2-yl)(2- (((5-fluoropyridin-2- yl)oxy)methyl)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone 113

3400 4800 (±)-(2-(((5- fluoropyridin-2- yl)oxy)methyl)-7- azabicyclo[2.2.1]heptan- 7-yl)(5-methoxy-3- (2H-1,2,3-triazol-2- yl)pyridin-2- yl)methanone 114

20 48 73 (±)-(2-(((5- fluoropyridin-2- yl)oxy)methyl)-7- azabicyclo[2.2.1]heptan- 7-yl)(5-methoxy-2- (2H-1,2,3-triazol-2- yl)phenyl)methanone 115

57 78 108 (±)-(2-fluoro-6-(2H- 1,2,3-triazol-2- yl)phenyl)(2-(((5- fluoropyridin-2- yl)oxy)methyl)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone 116

142 250 315 (±)-(4-fluoro-2-(2H- 1,2,3-triazol-2- yl)phenyl)(2-(((5- fluoropyridin-2- yl)oxy)methyl)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone 117

62 82 245 (±)-(3-fluoro-2-(2H- 1,2,3-triazol-2- yl)phenyl)(2-(((5- fluoropyridin-2- yl)oxy)methyl)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone 118

440 2200 (±)-(3-ethoxy-6- methylpyridin-2-yl)(2- (((5-fluoropyridin-2- yl)oxy)methyl)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone 119

500 1300 (±)-(2-(((5- fluoropyridin-2- yl)oxy)methyl)-7- azabicyclo[2.2.1]heptan- 7-yl)(4-methoxy-2- (2H-1,2,3-triazol-2- yl)phenyl)methanone 120

15 14 124 (±)-(5-chloro-2-(2H- 1,2,3-triazol-2- yl)phenyl)(2-(((5- fluoropyridin-2- yl)oxy)methyl)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone 121

78 68 340 (±)-(2-(((5- fluoropyridin-2- yl)oxy)methyl)-7- azabicyclo[2.2.1]heptan- 7-yl)(4-methyl-2- (2H-1,2,3-triazol-2- yl)phenyl)methanone 122

118 154 1000 (±)-(2-(((5- fluoropyridin-2- yl)oxy)methyl)-7- azabicyclo[2.2.1]heptan- 7-yl)(4-methyl-2- (pyrimidin-2- yl)phenyl)methanone 123

400 286 (±)-(2-(((5- fluoropyridin-2- yl)oxy)methyl)-7- azabicyclo[2.2.1]hepta n-7-yl)(2-methyl-6- (pyrimidin-2- yl)phenyl)methanone 124

83 52 355 (±)-(3-fluoro-2- (pyrimidin-2- yl)phenyl)(-2-(((5- fluoropyridin-2- yl)oxy)methyl)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone 125

47 29 132 (±)-(2-(((5- fluoropyridin-2- yl)oxy)methyl)-7- azabicyclo[2.2.1]heptan- 7-yl)(3-methyl-2- (2H-1,2,3-triazol-2- yl)phenyl)methanone 126

23 27 231 (±)-(2-(((5- fluoropyridin-2- yl)oxy)methyl)-7- azabicyclo[2.2.1]heptan- 7-yl)(5- (hydroxymethyl)-2- (2H-1,2,3-triazol-2- yl)phenyl)methanone 127

190 1100 (±)-(2-(3-methyl- 1,2,4-oxadiazol-5- yl)phenyl)(2-((pyridin- 2-yloxy)methyl)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone 128

5700 10000 (±)-(6-methyl-2-(2H- 1,2,3-triazol-2- yl)pyridin-3-yl)(2- ((pyridin-2- yloxy)methyl)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone 129

190 1000 (±)-(3-fluoro-2-(2H- 1,2,3-triazol-2- yl)phenyl)(2-((pyridin- 2-yloxy)methyl)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone 130

3700 7199 (±)-(6-methyl-2-(1H- 1,2,3-triazol-1- yl)pyridin-3-yl)(2- ((pyridin-2- yloxy)methyl)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone 131

10000 10000 (±)-(6-methyl-2-(2H- 1,2,3-triazol-2- yl)pyridin-3-yl)(2- (((4- (trifluoromethyl)pyrimidin- 2-yl)oxy)methyl)- 7- azabicyclo[2.2.1]heptan- 7-yl)methanone 132

10000 7399 (±)-(6-methyl-2-(1H- 1,2,3-triazol-1- yl)pyridin-3-yl)(2- (((4- (trifluoromethyl)pyrimidin- 2-yl)oxy)methyl)- 7- azabicyclo[2.2.1]heptan- 7-yl)methanone 133

1400 950 (±)-(2-(3-methyl- 1,2,4-oxadiazol-5- yl)phenyl)(2-(((4- (trifluoromethyl)pyrimidin- 2-yl)oxy)methyl)- 7- azabicyclo[2.2.1]heptan- 7-yl)methanone 134

1500 690 (±)-(3-fluoro-2-(2H- 1,2,3-triazol-2- yl)phenyl)(2-(((4- (trifluoromethyl)pyrimidin- 2-yl)oxy)methyl)- 7- azabicyclo[2.2.1]heptan- 7-yl)methanone 135

5400 3900 (±)-(6-methyl-2-(2H- 1,2,3-triazol-2- yl)pyridin-3-yl)(2- (((5-methylpyridin-2- yl)oxy)methyl)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone 136

6800 1200 (±)-(6-methyl-2-(1H- 1,2,3-triazol-1- yl)pyridin-3-yl)(2- (((5-methylpyridin-2- yl)oxy)methyl)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone 137

950 425 (±)-(2-(3-methyl- 1,2,4-oxadiazol-5- yl)phenyl)(2-(((5- methylpyridin-2- yl)oxy)methyl)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone 138

606 250 (±)-(3-fluoro-2-(2H- 1,2,3-triazol-2- yl)phenyl)(2-(((5- methylpyridin-2- yl)oxy)methyl)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone 139

4399 6500 (±)-(6-methyl-2-(2H- 1,2,3-triazol-2- yl)pyridin-3-yl)(2- (((6-methylpyridin-2- yl)oxy)methyl)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone 140

3100 2300 (±)-(6-methyl-2-(1H- 1,2,3-triazol-1- yl)pyridin-3-yl)(2- (((6-methylpyridin-2- yl)oxy)methyl)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone 141

280 300 (±)-(2-(3-methyl- 1,2,4-oxadiazol-5- yl)phenyl)(2-(((6- methylpyridin-2- yl)oxy)methyl)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone 142

207 300 (±)-(3-fluoro-2-(2H- 1,2,3-triazol-2- yl)phenyl)(2-(((6- methylpyridin-2- yl)oxy)methyl)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone 143

3900 4600 (±)-(6-methyl-2-(2H- 1,2,3-triazol-2- yl)pyridin-3-yl)(2- (((6- (trifluoromethyl)pyridin- 2-yl)oxy)methyl)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone 144

3600 3200 (±)-(6-methyl-2-(1H- 1,2,3-triazol-1- yl)pyridin-3-yl)(2- (((6- (trifluoromethyl)pyridin- 2-yl)oxy)methyl)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone 145

340 330 (±)-(2-(3-methyl- 1,2,4-oxadiazol-5- yl)phenyl)(2-(((6- (trifluoromethyl)pyridin- 2-yl)oxy)methyl)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone 146

180 196 (±)-(3-fluoro-2-(2H- 1,2,3-triazol-2- yl)phenyl)(2-(((6- (trifluoromethyl)pyridin- 2-yl)oxy)methyl)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone 147

(±)-(6-methyl-2-(2H- 1,2,3-triazol-2- yl)pyridin-3-yl)(2- ((quinoxalin-2- yloxy)methyl)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone 148

6299 3200 (±)-(6-methyl-2-(1H- 1,2,3-triazol-1- yl)pyridin-3-yl)(2- ((quinoxalin-2- yloxy)methyl)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone 149

220 2000 (±)-(2-(3-methyl- 1,2,4-oxadiazol-5- yl)phenyl)(2- ((quinoxalin-2- yloxy)methyl)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone 150

180 990 (±)-(3-fluoro-2-(2H- 1,2,3-triazol-2- yl)phenyl)(2- ((quinoxalin-2- yloxy)methyl)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone 151

10000 10000 (±)-(2-(((4,6- dimethylpyrimidin-2- yl)oxy)methyl)-7- azabicyclo[2.2.1]heptan- 7-yl)(6-methyl-2- (2H-1,2,3-triazol-2- yl)pyridin-3- yl)methanone 152

10000 5899 (±)-(2-(((4,6- dimethylpyrimidin-2- yl)oxy)methyl)-7- azabicyclo[2.2.1]heptan- 7-yl)(6-methyl-2- (1H-1,2,3-triazol-1- yl)pyridin-3- yl)methanone 153

1100 440 (±)-(2-(((4,6- dimethylpyrimidin-2- yl)oxy)methyl)-7- azabicyclo[2.2.1]heptan- 7-yl)(2-(3-methyl- 1,2,4-oxadiazol-5- yl)phenyl)methanone 154

690 300 (±)-(2-(((4,6- dimethylpyrimidin-2- yl)oxy)methyl)-7- azabicyclo[2.2.1]heptan- 7-yl)(3-fluoro-2- (2H-1,2,3-triazol-2- yl)phenyl)methanone 155

1570 3600 (±)-(2-ethoxy-4- methylpyridin-3-yl)(2- ((pyridin-2- yloxy)methyl)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone 156

>10000 >10000 (±)-(6- methylimidazo[2,1- b]thiazol-5-yl)(2- ((pyridin-2- yloxy)methyl)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone 157

94 134 537 (±)-(5-bromo-2- ethoxypyridin-3-yl)(2- ((pyridin-2- yloxy)methyl)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone 158

2930 1780 (±)-(2-ethoxy-6- methylpyridin-3-yl)(2- ((pyridin-2- yloxy)methyl)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone 159

262 786 (±)-(7- hydroxyquinolin-8- yl)(2-((pyridin-2- yloxy)methyl)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone 160

8700 >10000 (±)-(2-ethoxy-5- phenylpyridin-3-yl)(2- ((pyridin-2- yloxy)methyl)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone 161

478 1450 (±)-(4-bromo-2- ethoxypyridin-3-yl)(2- ((pyridin-2- yloxy)methyl)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone 162

8500 >10000 (±)-(2-chloro-4- ethoxypyridin-3-yl)(2- ((pyridin-2- yloxy)methyl)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone 163

150 153 150 (±)-(2,4- diethoxypyridin-3- yl)(2-((pyridin-2- yloxy)methyl)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone 164

9 7 195 (3-ethoxyisoquinolin- 4-yl)((1S,2R,4R)-2- ((pyridin-2- yloxy)methyl)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone 165

409 550 (±)-(2- ethoxyphenyl)(2-(((5- fluoropyridin-2- yl)oxy)methyl)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone 166

106 1141 (±)-(5-fluoro-2-(2H- 1,2,3-triazol-2- yl)phenyl)(2- ((quinoxalin-2- yloxy)methyl)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone 167

9 14 (±)-5-methyl-2-(2H- 1,2,3-triazol-2- yl)phenyl)(2-(((5- methylpyridin-2- yl)oxy)methyl)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone 168

2300 7300 (±)-(6-methyl-2-(2H- 1,2,3-triazol-2- yl)pyridin-3-yl)(2- ((quinoxalin-2- yloxy)methyl)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone 169

8999 2526 (±)-(5-fluoro-2-(2H- 1,2,3-triazol-2- yl)phenyl)(2-((pyridin- 2-ylamino)methyl)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone 170

1965 512 (±)-(2-(((4,6- dimethylpyrimidin-2- yl)amino)methyl)-7- azabicyclo[2.2.1]heptan- 7-yl)(5-fluoro-2- (2H-1,2,3-triazol-2- yl)phenyl)methanone 171

1935 (±)-(5-fluoro-2-(2H- 1,2,3-triazol-2- yl)phenyl)(2-(((4- (trifluoromethyl)pyrimidin- 2- yl)amino)methyl)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone 172

686 (±)-(5-fluoro-2-(2H- 1,2,3-triazol-2- yl)phenyl)(2-(((6- (trifluoromethyl)pyridin- 2-yl)amino)methyl)- 7- azabicyclo[2.2.1]heptan- 7-yl)methanone 173

1260 3000 (±)-(3-fluoro-2- methoxyphenyl)(2- (((5-fluoropyridin-2- yl)oxy)methyl)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone 174

373 1000 (±)-(5-fluoro-2-(2H- 1,2,3-triazol-2- yl)phenyl)(2- ((quinoxalin-2- ylamino)methyl)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone 175

2500 4000 (±)-(2-(((5- fluoropyrimidin-2- yl)oxy)methyl)-7- azabicyclo[2.2.1]heptan- 7-yl)(6-methyl-3- (pyrimidin-2- yl)pyridin-2- yl)methanone 176

119 150 202 (±)-(6-methyl-3-(2H- 1,2,3-triazol-2- yl)pyridin-2-yl)(2- (((3-methylpyridin-2- yl)oxy)methyl)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone 177

535 4000 (±)-(2-(((5- fluoropyridin-2- yl)oxy)methyl)-7- azabicyclo[2.2.1]heptan- 7-yl)(6-methyl-3-(4- methyloxazol-2- yl)pyridin-2- yl)methanone 178

964 >10000 (6-methyl-3-(4- methyloxazol-2- yl)pyridin-2- yl)((1S,2R,4R)-2- ((pyridin-2- yloxy)methyl)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone 179

((1S,2R,4R)-2-(((5- fluoropyrimidin-2- yl)oxy)methyl)-7- azabicyclo[2.2.1]heptan- 7-yl)(6-methyl-3-(4- methyloxazol-2- yl)pyridin-2- yl)methanone 180

33 32 (±)-(5-methyl-2-(2H- 1,2,3-triazol-2- yl)phenyl)(2-(((6- methyl-2- (trifluoromethyl)pyrimidin- 4-yl)oxy)methyl)- 7- azabicyclo[2.2.1]heptan- 7-yl)methanone 181

34 28 700 (2-(2H-1,2,3-triazol-2- yl)phenyl)(1S,2R,4R)- 2-((5- (trifluoromethyl)pyrazin- 2-yl)amino)-7- azabicyclo[2.2.1]hepta n-7-yl)methanone 182

47 38 1100 (±)-((2-(2H-1,2,3- triazol-2-yl)phenyl)(2- ((5- (trifluoromethyl)pyrazin- 2-yl)amino)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone 183a

>10000 >10000 (2-(2H-1,2,3-triazol-2- yl)phenyl)((1S,2R,4R)- 2-((5- (trifluoromethyl)pyrazin- 2-yl)amino)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone 183b

34 28 700 (2-(2H-1,2,3-triazol-2- yl)phenyl)((1R,2S,4S)- 2-((5- (trifluoromethyl)pyrazin- 2-yl)amino)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone 184

189 349 4100 (±)-(5-methyl-3-(2H- 1,2,3-triazol-2- yl)pyridin-2-yl)(2-((5- (trifluoromethyl)pyrazin- 2-yl)amino)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone 185

1500 2700 (±)-(5-methyl-3-(1H- 1,2,3-triazol-1- yl)pyridin-2-yl)(2-((5- (trifluoromethyl)pyrazin- 2-yl)amino)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone 186

134 164 1200 (±)-(6-methyl-3-(2H- 1,2,3-triazol-2- yl)pyridin-2-yl)(2-((5- (trifluoromethyl)pyrazin- 2-yl)amino)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone 187

81 48 620 (±)-(6-methyl-3-(2H- 1,2,3-triazol-2- yl)pyridin-2-yl)(2-((5- (trifluoromethyl)pyridin- 2-yl)amino)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone 188

295 1500 (±)-(5-methyl-3-(2H- 1,2,3-triazol-2- yl)pyridin-2-yl)(2-((5- (trifluoromethyl)pyridin- 2-yl)amino)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone 189

766 1500 (±)-(6-methyl-2-(2H- 1,2,3-triazol-2- yl)pyridin-3-yl)(2-((5- (trifluoromethyl)pyridin- 2-yl)amino)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone 190

589 1200 (±)-(6-methyl-2-(1H- 1,2,3-triazol-1- yl)pyridin-3-yl)(2-((5- (trifluoromethyl)pyridin- 2-yl)amino)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone 191

257 8800 (±)-(4-methoxy-2- (2H-1,2,3-triazol-2- yl)phenyl)(2-((5- (trifluoromethyl)pyridin- 2-yl)amino)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone 192

60 52 1500 (±)-(3-fluoro-2- (pyrimidin-2- yl)phenyl)(2-((5- (trifluoromethyl)pyridin- 2-yl)amino)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone 193

2900 >10000 (±)-((3-fluoro-2- methoxyphenyl)(2-((5- (trifluoromethyl)pyridin- 2-yl)amino)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone 194

450 800 (±)-(3-ethoxy-6- methylpyridin-2-yl)(2- ((5- (trifluoromethyl)pyridin- 2-yl)amino)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone 195

57 37 325 (±)-(6-methyl-3- (pyrimidin-2- yl)pyridin-2-yl)(2-((5- (trifluoromethyl)pyridin- 2-yl)amino)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone 196

59 61 1500 (±)-(2-(2H-1,2,3- triazol-2-yl)phenyl)(2- ((5- (trifluoromethyl)pyridin- 2-yl)amino)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone 197

8999 862 (±)-(2-((4,6- dimethylpyrimidin-2- yl)amino)-7- azabicyclo[2.2.1]heptan- 7-yl)(5-fluoro-2- (2H-1,2,3-triazol-2- yl)phenyl)methanone 198

1411 704 (±)-(2-((4,6- dimethylpyrimidin-2- yl)amino)-7- azabicyclo[2.2.1]heptan- 7-yl)(2-fluoro-6- (2H-1,2,3-triazol-2- yl)phenyl)methanone 199

1634 553 (±)-(2-((4,6- dimethylpyrimidin-2- yl)amino)-7- azabicyclo[2.2.1]heptan- 7-yl)(4-fluoro-2- (2H-1,2,3-triazol-2- yl)phenyl)methanone 200

1100 552 (±)-(2-((4,6- dimethylpyrimidin-2- yl)amino)-7- azabicyclo[2.2.1]heptan- 7-yl)(6-methyl-3- (pyrimidin-2- yl)pyridin-2- yl)methanone 201

3700 1100 (±)-(2-((4,6- dimethylpyrimidin-2- yl)amino)-7- azabicyclo[2.2.1]heptan- 7-yl)(6-methyl-3- (2H-1,2,3-triazol-2- yl)pyridin-2- yl)methanone 202

760 444 (±)-(2-(2H-1,2,3- triazol-2-yl)phenyl)(2- ((4,6- dimethylpyrimidin-2- yl)amino)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone 203

>10000 490 (±)-(2-((4,6- dimethylpyrimidin-2- yl)amino)-7- azabicyclo[2.2.1]hepta n-7-yl)(3-ethoxy-6- methylpyridin-2- yl)methanone 204

33 25 220 (±)-(2-(2H-1,2,3- triazol-2-yl)phenyl)(2- (quinoxalin-2- ylamino)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone 205

79 50 168 (±)-(6-methyl-3-(2H- 1,2,3-triazol-2- yl)pyridin-2-yl)(2- (quinoxalin-2- ylamino)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone 206

1200 1500 (±)-(3-fluoro-2- methoxyphenyl)(2- (quinoxalin-2- ylamino)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone 207

120 95 64 (±)-(3-ethoxy-6- methylpyridin-2-yl)(2- (quinoxalin-2- ylamino)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone 208

26 30 90 (±)-(6-methyl-3- (pyrimidin-2- yl)pyridin-2-yl)(2- (quinoxalin-2- ylamino)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone 209

1100 736 (±)-(2-(2H-1,2,3- triazol-2-yl)phenyl)(2- ((6- (trifluoromethyl)pyridin- 2-yl)amino)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone 210

211 128 (±)-((2-(2H-1,2,3- triazol-2-yl)phenyl)(2- ((4- (trifluoromethyl)pyridin- 2-yl)amino)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone 211

110 55 1800 (±)-(2-(2H-1,2,3- triazol-2-yl)phenyl)(2- ((5-chloropyridin-2- yl)amino)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone 212

734 4900 (±)-(2-(2H-1,2,3- triazol-2-yl)phenyl)(2- ((6- (trifluoromethyl)pyridazin- 3-yl)amino)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone 213

2800 7501 (±)-(2-(2H-1,2,3- triazol-2-yl)phenyl)(2- ((5-methoxypyridin-2- yl)amino)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone 214

500 3100 (±)-(2-(2H-1,2,3- triazol-2-yl)phenyl)(2- ((5-methylpyridin-2- yl)amino)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone 215

1700 8999 (±)-(2-(2H-1,2,3- triazol-2-yl)phenyl)(2- (pyridin-2-ylamino)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone 216

99 71 475 (±)-(2-(2H-1,2,3- triazol-2-yl)phenyl)(2- ((5- chlorobenzo[d]oxazol- 2-yl)amino)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone 217

59 40 770 (±)-(2-((5- bromopyridin-2- yl)amino)-7- azabicyclo[2.2.1]heptan- 7-yl)(6-methyl-3- (pyrimidin-2- yl)pyridin-2- yl)methanone 218

2700 6700 (±)-(2-((5- bromopyridin-2- yl)amino)-7- azabicyclo[2.2.1]heptan- 7-yl)(3-fluoro-2- methoxyphenyl)methanone 219

257 1700 (±)-(2-((5- bromopyridin-2- yl)amino)-7- azabicyclo[2.2.1]heptan- 7-yl)(3-ethoxy-6- methylpyridin-2- yl)methanone 220

38 26 1100 (±)-(2-((5- bromopyridin-2- yl)amino)-7- azabicyclo[2.2.1]heptan- 7-yl)(6-methyl-3- (2H-1,2,3-triazol-2- yl)pyridin-2- yl)methanone 221

172 200 3300 (±)-(2-(2H-1,2,3- triazol-2-yl)phenyl)(2- ((5- (trifluoromethyl)pyrimidin- 2-yl)amino)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone 222

4800 >10000 (±)-(3-fluoro-2- methoxyphenyl)(2-((5- (trifluoromethyl)pyrimidin- 2-yl)amino)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone 223

550 4000 (±)-(6-methyl-3-(2H- 1,2,3-triazol-2- yl)pyridin-2-yl)(2-((5- (trifluoromethyl)pyrimidin- 2-yl)amino)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone 224

2500 7399 (±)-(3-ethoxy-6- methylpyridin-2-yl)(2- ((5- (trifluoromethyl)pyrimidin- 2-yl)amino)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone 225

530 3300 (±)-(6-methyl-3- (pyrimidin-2- yl)pyridin-2-yl)(2-((5- (trifluoromethyl)pyrimidin- 2-yl)amino)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone 226

>10000 >10000 (±)-(3-fluoro-2- methoxyphenyl)(2-((5- (trifluoromethyl)pyrimidin- 2-yl)amino)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone 227

>10000 >10000 (±)-(3-ethoxy-6- methylpyridin-2-yl)(2- ((5- (trifluoromethyl)pyrimidin- 2-yl)amino)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone 228

>10000 >10000 (±)-(6-methyl-3-(2H- 1,2,3-triazol-2- yl)pyridin-2-yl)(2-((5- (trifluoromethyl)pyrimidin- 2-yl)amino)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone 229

>10000 >10000 (±)-(3-ethoxy-6- methylpyridin-2-yl)(2- (quinoxalin-2- ylamino)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone 230

>10000 >10000 (±)-(6-methyl-3-(2H- 1,2,3-triazol-2- yl)pyridin-2-yl)(2- (quinoxalin-2- ylamino)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone 231

>10000 >10000 (±)-(3-fluoro-2- methoxyphenyl)(2- (quinoxalin-2- ylamino)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone 232

(±)-(2-((5- bromopyridin-2- yl)amino)-7- azabicyclo[2.2.1]heptan- 7-yl)(6-methyl-3- (2H-1,2,3-triazol-2- yl)pyridin-2- yl)methanone 233

(±)-(2-((5- bromopyridin-2- yl)amino)-7- azabicyclo[2.2.1]heptan- 7-yl)(3-ethoxy-6- methylpyridin-2- yl)methanone 234

(±)-(2-((5- bromopyridin-2- yl)amino)-7- azabicyclo[2.2.1]heptan- 7-yl)(3-fluoro-2- methoxyphenyl)methanone 235

>10000 >10000 (±)-((2-(2H-1,2,3- triazol-2-yl)phenyl)(2- ((4- (trifluoromethyl)pyridin- 2-yl)amino)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone 236

>10000 >10000 (±)-(2-((5- fluoropyridin-2- yl)amino)-7- azabicyclo[2.2.1]heptan- 7-yl)(6-methyl-3- (2H-1,2,3-triazol-2- yl)pyridin-2- yl)methanone 237

>10000 >10000 (±)-(3-fluoro-2- methoxyphenyl)(2-((5- fluoropyridin-2- yl)amino)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone 238

16 16 955 (3-fluoro-2- (pyrimidin-2- yl)phenyl)((1S,2R,4R)- 2-((5- (trifluoromethyl)pyrazin- 2-yl)amino)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone 239

22 19 490 (2-ethoxynaphthalen- 1-yl)((1S,2R,4R)-2- ((5- (trifluoromethyl)pyrazin- 2-yl)amino)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone 240

400 2100 isoquinolin-4- yl((1S,2R,4R)-2-((5- (trifluoromethyl)pyrazin- 2-yl)amino)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone 241

134 159 5064 (4-methoxy-2-(2H- 1,2,3-triazol-2- yl)phenyl)((1S,2R,4R)- 2-((5- (trifluoromethyl)pyrazin- 2-yl)amino)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone 242

31 41 239 (2-methoxy-6-(2H- 1,2,3-triazol-2- yl)phenyl)((1S,2R,4R)- 2-((5- (trifluoromethyl)pyrazin- 2-yl)amino)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone 243

34 45 723 (5-fluoro-2- (pyrimidin-2- yl)phenyl)((1S,2R,4R)- 2-((5- (trifluoromethyl)pyrazin- 2-yl)amino)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone 244

74 46 235 (5-(4-fluorophenyl)-2- methylthiazol-4- yl)((1S,2R,4R)-2-((5- (trifluoromethyl)pyrazin- 2-yl)amino)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone 245

10 7 288 (3-methyl-2-(2H- 1,2,3-triazol-2- yl)phenyl)((1S,2R,4R)- 2-((5- (trifluoromethyl)pyrazin- 2-yl)amino)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone 246

29 17 1022 (3-ethoxyisoquinolin- 4-yl)((1S,2R,4R)-2- ((5- (trifluoromethyl)pyrazin- 2-yl)amino)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone 247

420 1130 (6-methyl-2-(2H- 1,2,3-triazol-2- yl)pyridin-3- yl)((1S,2R,4R)-2-((5- (trifluoromethyl)pyrazin- 2-yl)amino)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone 248

153 119 >10000 (6-methyl-2-(1H- 1,2,3-triazol-1- yl)pyridin-3- yl)((1S,2R,4R)-2-((5- (trifluoromethyl)pyrazin- 2-yl)amino)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone 249

57 54 5600 (4-methoxy-2- (pyrimidin-2- yl)phenyl)((1S,2R,4R)- 2-((5- (trifluoromethyl)pyrazin- 2-yl)amino)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone 250

5649 >10000 (1H- benzo[d]imidazol-2- yl)((1S,2R,4R)-2-((5- (trifluoromethyl)pyrazin- 2-yl)amino)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone 251

520 5300 (1-methyl-1H- benzo[d]imidazol-2- yl)((1S,2R,4R)-2-((5- (trifluoromethyl)pyrazin- 2-yl)amino)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone 252

45 27 1230 (3-fluoro-2-(2H-1,2,3- triazol-2- yl)phenyl)((1S,2R,4R)- 2-((5- (trifluoromethyl)pyrazin- 2-yl)amino)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone 253

155 152 9601 (4-(difluoromethoxy)- 2-(2H-1,2,3-triazol-2- yl)phenyl)((1S,2R,4R)- 2-((5- (trifluoromethyl)pyrazin- 2-yl)amino)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone 254

23 20 377 (3-fluoro-2-(3-methyl- 1,2,4-oxadiazol-5- yl)phenyl)((1S,2R,4R)- 2-((5- (trifluoromethyl)pyrazin- 2-yl)amino)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone 255

32 29 265 (5-methoxy-2-(2H- 1,2,3-triazol-2- yl)phenyl)((1S,2R,4R)- 2-((5- (trifluoromethyl)pyrazin- 2-yl)amino)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone 256

84 60 1100 (5-fluoro-2-(2H-1,2,3- triazol-2- yl)phenyl)((1S,2R,4R)- 2-((5- (trifluoromethyl)pyrazin- 2-yl)amino)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone 257

85 102 3200 (4-fluoro-2-(2H-1,2,3- triazol-2- yl)phenyl)((1S,2R,4R)- 2-((5- (trifluoromethyl)pyrazin- 2-yl)amino)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone 258

42 48 690 (2-fluoro-6-(2H-1,2,3- triazol-2- yl)phenyl)((1S,2R,4R)- 2-((5- (trifluoromethyl)pyrazin- 2-yl)amino)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone 259

>10000 >10000 (6-methylimidazo[2,1- b]thiazol-5- yl)((1S,2R,4R)-2-((5- (trifluoromethyl)pyrazin- 2-yl)amino)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone 260

14 10 519 (3-fluoro-2-(oxazol-2- yl)phenyl)((1S,2R,4R)- 2-((5- (trifluoromethyl)pyrazin- 2-yl)amino)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone 261

>10000 5000 (2-((4,6- dimethylpyrimidin-2- yl)amino)-7- azabicyclo[2.2.1]heptan- 7-yl)(3-fluoro-2- methoxyphenyl)methanone 262

106 175 4200 (3-fluoro-2-(pyridazin- 3- yl)phenyl)((1S,2R,4R)- 2-((5- (trifluoromethyl)pyrazin- 2-yl)amino)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone 263

44 41 1100 (3-methyl-2- (pyridazin-3- yl)phenyl)((1S,2R,4R)- 2-((5- (trifluoromethyl)pyrazin- 2-yl)amino)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone 264

1400 >10000 (3-fluoro-2-(pyridazin- 4- yl)phenyl)((1S,2R,4R)- 2-((5- (trifluoromethyl)pyrazin- 2-yl)amino)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone 265

20 23 188 (3-fluoro-2-(pyrazin- 2- yl)phenyl)((1S,2R,4R)- 2-((5- (trifluoromethyl)pyrazin- 2-yl)amino)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone 266

5 7 121 (3-methyl-2-(oxazol- 2- yl)phenyl)((1S,2R,4R)- 2-((5- (trifluoromethyl)pyrazin- 2-yl)amino)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone 267

33 61 1700 (4-fluoro-2- (pyrimidin-2- yl)phenyl)((1S,2R,4R)- 2-((5- (trifluoromethyl)pyrazin- 2-yl)amino)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone 268

450 3700 (3-fluoro-2-(pyridin-4- yl)phenyl)((1S,2R,4R)- 2-((5- (trifluoromethyl)pyrazin- 2-yl)amino)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone 269

48 111 1700 (3-fluoro-2-(2H-1,2,3- triazol-2- yl)phenyl)((1S,2R,4R)- 2-((5- (trifluoromethyl)pyrimidin- 2-yl)amino)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone 270

325 145 ((1S,2R,4R)-2-((3- bromoimidazo[1,2- a]pyrazin-8-yl)amino)- 7- azabicyclo[2.2.1]heptan- 7-yl)(3-fluoro-2- (pyrimidin-2- yl)phenyl)methanone 271

41 42 2300 (3-fluoro-2- (pyrimidin-2- yl)phenyl)((1S,2R,4R)- 2-((5- (trifluoromethyl)pyrimidin- 2-yl)amino)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone 272

21 26 742 (3-methyl-2-(2H- 1,2,3-triazol-2- yl)phenyl)((1S,2R,4R)- 2-((5- (trifluoromethyl)pyrimidin- 2-yl)amino)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone 273

17 12 328 (3-methyl-2- (pyrimidin-2- yl)phenyl)((1S,2R,4R)- 2-((5- (trifluoromethyl)pyrazin- 2-yl)amino)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone 274

>10000 2560 (3-fluoro-2- (pyrimidin-2- yl)phenyl)((1S,2R,4R)- 2-((3- (trifluoromethyl)- [1,2,4]triazolo[4,3- a]pyrazin-8-yl)amino)- 7- azabicyclo[2.2.1]heptan- 7-yl)methanone 275

>10000 >10000 methyl 5- (((1S,2R,4R)-7-(3- fluoro-2-(pyrimidin-2- yl)benzoyl)-7- azabicyclo[2.2.1]heptan- 2- yl)amino)pyrazine-2- carboxylate 276

133 97 2500 (2-iodo-3- methylphenyl)((1S,2R, 4R)-2-((5- (trifluoromethyl)pyrimidin- 2-yl)amino)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone 277

457 7399 (3-fluoro-2- iodophenyl)((1S,2R,4R)- 2-((5- (trifluoromethyl)pyrimidin- 2-yl)amino)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone 278

87 77 934 (3-fluoro-2- (pyrimidin-2- yl)phenyl)((1S,2R,4R)- 2-((5-methylpyrazin- 2-yl)amino)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone 279

15 8 1100 (3-fluoro-2- (pyrimidin-2- yl)phenyl)((1S,2R,4R)- 2-((5- (trifluoromethyl)pyridin- 2-yl)amino)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone 280

39 37 1300 (4-fluoro-2- (pyrimidin-2- yl)phenyl)((1S,2R,4R)- 2-((5- (trifluoromethyl)pyridin- 2-yl)amino)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone 281

21 17 1200 (3-methyl-2- (pyrimidin-2- yl)phenyl)((1S,2R,4R)- 2-((5- (trifluoromethyl)pyrimidin- 2-yl)amino)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone 282

486 >10000 (3-fluoro-2- (pyrimidin-2- yl)phenyl)((1S,2R,4R)- 2-(methyl(5- (trifluoromethyl)pyrazin- 2-yl)amino)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone 283

14 9 417 (3-methyl-2-(oxazol- 2- yl)phenyl)((1S,2R,4R)- 2-((5- (trifluoromethyl)pyrimidin- 2-yl)amino)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone 284

29 27 1700 (3-fluoro-2-(oxazol-2- yl)phenyl)((1S,2R,4R)- 2-((5- (trifluoromethyl)pyrimidin- 2-yl)amino)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone 285

720 >10000 (±)-(3-fluoro-2- (pyrimidin-2- yl)phenyl)(2-((5- (trifluoromethyl)pyrimidin- 2-yl)oxy)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone 286

>10000 >10000 (±)-(3-fluoro-2- (pyrimidin-2- yl)phenyl)(2-((5- (trifluoromethyl)pyrimidin- 2-yl)oxy)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone 287

472 767 (3-ethoxy-6- methylpyridin-2- yl)((1S,2R,4R)-2-((5- (trifluoromethyl)pyrazin- 2-yl)amino)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone 288

94 128 1900 (3-(2H-1,2,3-triazol-2- yl)pyridin-2- yl)((1S,2R,4R)-2-((5- (trifluoromethyl)pyrazin- 2-yl)amino)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone 289

13 32 173 (2-methoxy-6- (pyrimidin-2- yl)phenyl)((1S,2R,4R)- 2-((5- (trifluoromethyl)pyrazin- 2-yl)amino)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone 290

21 19 558 (2-fluoro-6- (pyrimidin-2- yl)phenyl)((1S,2R,4R)- 2-((5- (trifluoromethyl)pyrazin- 2-yl)amino)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone 291

15 35 425 (7-ethoxyquinolin-8- yl)((1S,2R,4R)-2-((5- (trifluoromethyl)pyrazin- 2-yl)amino)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone 292

>10000 >10000 (2-(1,4-dimethyl-1H- pyrazol-5-yl)-6- methoxyphenyl) ((1S,2R,4R)- 2-((5- (trifluoromethyl)pyrazin- 2-yl)amino)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone 293

23 37 1100 (3-methyl-2-(pyridin- 2- yl)phenyl)((1S,2R,4R)- 2-((5- (trifluoromethyl)pyrimidin- 2-yl)amino)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone 294

21 15 1200 (3-fluoro-2-(2H-1,2,3- triazol-2- yl)phenyl)((1S,2R,4R)- 2-((5- (trifluoromethyl)pyridin- 2-yl)amino)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone 295

9 8 257 (3-methyl-2-(2H- 1,2,3-triazol-2- yl)phenyl)((1S,2R,4R)- 2-((5- (trifluoromethyl)pyridin- 2-yl)amino)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone 296

5 6 114 (3-methyl-2-(oxazol- 2- yl)phenyl)((1S,2R,4R)- 2-((5- (trifluoromethyl)pyridin- 2-yl)amino)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone 297

>10000 >10000 (3-fluoro-2- (pyrimidin-2- yl)phenyl)((1R,2S,4S)- 2-((5- (trifluoromethyl)pyrazin- 2-yl)amino)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone 298

(3-fluoro-2-(oxazol-2- yl)phenyl)((1S,2R,4R)- 2-((5- (trifluoromethyl)pyridin- 2-yl)amino)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone 299

(3-methyl-2- (pyrimidin-2- yl)phenyl)((1S,2R,4R)- 2-((5- (trifluoromethyl)pyridin- 2-yl)amino)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone 300

(3-chloro-2- (pyrimidin-2- yl)phenyl)((1S,2R,4R)- 2-((5- (trifluoromethyl)pyrazin- 2-yl)amino)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone 301

((1S,2R,4R)-2-((5- bromopyridin-2- yl)amino)-7- azabicyclo[2.2.1]heptan- 7-yl)(3-fluoro-2- (oxazol-2- yl)phenyl)methanone 302

((1S,2R,4R)-2-((5- bromopyridin-2- yl)amino)-7- azabicyclo[2.2.1]heptan- 7-yl)(3-methyl-2- (oxazol-2- yl)phenyl)methanone 303

((1S,2R,4R)-2-((5- bromopyridin-2- yl)amino)-7- azabicyclo[2.2.1]heptan- 7-yl)(3-fluoro-2- (pyrimidin-2- yl)phenyl)methanone 304

((1S,2R,4R)-2-((5- bromopyridin-2- yl)amino)-7- azabicyclo[2.2.1]heptan- 7-yl)(3-methyl-2- (pyrimidin-2- yl)phenyl)methanone 305

((1S,2R,4R)-2-((5- bromopyridin-2- yl)amino)-7- azabicyclo[2.2.1]heptan- 7-yl)(3-fluoro-2- (2H-1,2,3-triazol-2- yl)phenyl)methanone 306

((1S,2R,4R)-2-((5- bromopyridin-2- yl)amino)-7- azabicyclo[2.2.1]heptan- 7-yl)(3-methyl-2- (2H-1,2,3-triazol-2- yl)phenyl)methanone 307

((1S,2R,4R)-2-((5- bromopyrazin-2- yl)amino)-7- azabicyclo[2.2.1]heptan- 7-yl)(3-fluoro-2- (oxazol-2- yl)phenyl)methanone 308

((1S,2R,4R)-2-((5- bromopyrazin-2- yl)amino)-7- azabicyclo[2.2.1]heptan- 7-yl)(3-methyl-2- (oxazol-2- yl)phenyl)methanone 309

((1S,2R,4R)-2-((5- bromopyrazin-2- yl)amino)-7- azabicyclo[2.2.1]heptan- 7-yl)(3-fluoro-2- (pyrimidin-2- yl)phenyl)methanone 310

((1S,2R,4R)-2-((5- bromopyrazin-2- yl)amino)-7- azabicyclo[2.2.1]hepta n-7-yl)(3-methyl-2- (pyrimidin-2- yl)phenyl)methanone 311

((1S,2R,4R)-2-((5- bromopyrazin-2- yl)amino)-7- azabicyclo[2.2.1]heptan- 7-yl)(3-fluoro-2- (2H-1,2,3-triazol-2- yl)phenyl)methanone 312

((1S,2R,4R)-2-((5- bromopyrazin-2- yl)amino)-7- azabicyclo[2.2.1]heptan- 7-yl)(3-methyl-2- (2H-1,2,3-triazol-2- yl)phenyl)methanone 313

((1S,2R,4R)-2-((5- bromopyrimidin-2- yl)amino)-7- azabicyclo[2.2.1]heptan- 7-yl)(3-fluoro-2- (oxazol-2- yl)phenyl)methanone 314

((1S,2R,4R)-2-((5- bromopyrimidin-2- yl)amino)-7- azabicyclo[2.2.1]heptan- 7-yl)(3-methyl-2- (oxazol-2- yl)phenyl)methanone 315

((1S,2R,4R)-2-((5- bromopyrimidin-2- yl)amino)-7- azabicyclo[2.2.1]heptan- 7-yl)(3-fluoro-2- (pyrimidin-2- yl)phenyl)methanone 316

((1S,2R,4R)-2-((5- bromopyrimidin-2- yl)amino)-7- azabicyclo[2.2.1]heptan- 7-yl)(3-methyl-2- (pyrimidin-2- yl)phenyl)methanone 317

((1S,2R,4R)-2-((5- bromopyrimidin-2- yl)amino)-7- azabicyclo[2.2.1]heptan- 7-yl)(3-fluoro-2- (2H-1,2,3-triazol-2- yl)phenyl)methanone 318

((1S,2R,4R)-2-((5- bromopyrimidin-2- yl)amino)-7- azabicyclo[2.2.1]heptan- 7-yl)(3-methyl-2- (2H-1,2,3-triazol-2- yl)phenyl)methanone 319

(3-methyl-2-(pyridin- 2- yl)phenyl)((1S,2R,4R)- 2-((5- (trifluoromethyl)pyridin- 2-yl)amino)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone 320

(3-fluoro-2-(pyridin-2- yl)phenyl)((1S,2R,4R)- 2-((5- (trifluoromethyl)pyridin- 2-yl)amino)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone 321

(3-fluoro-2-(pyridin-2- yl)phenyl)((1S,2R,4R)- 2-((5- (trifluoromethyl)pyrimidin- 2-yl)amino)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone 322

(3-methyl-2-(pyridin- 2- yl)phenyl)((1S,2R,4R)- 2-((5- (trifluoromethyl)pyrazin- 2-yl)amino)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone 323

(3-fluoro-2-(pyridin-2- yl)phenyl)((2S)-2-((5- (trifluoromethyl)pyrazin- 2-yl)amino)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone 324

(3-fluoro-2- (pyrimidin-2- yl)phenyl)((1S,2R,4R)- 2-((5- (trifluoromethyl)pyridin- 2-yl)oxy)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone 325

(2-methoxy-6- (pyrimidin-2- yl)phenyl)((1S,2R,4R)- 2-((5- (trifluoromethyl)pyridin- 2-yl)oxy)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone 326

(5-fluoro-2-(2H-1,2,3- triazol-2- yl)phenyl)((1S,2R,4R)- 2-((5- (trifluoromethyl)pyridin- 2-yl)oxy)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone 327

(4-methyl-2-(2H- 1,2,3-triazol-2- yl)phenyl)((1S,2R,4R)- 2-((5- (trifluoromethyl)pyridin- 2-yl)oxy)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone 328

(3-methyl-2-(2H- 1,2,3-triazol-2- yl)phenyl)((1S,2R,4R)- 2-((5- (trifluoromethyl)pyridin- 2-yl)oxy)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone 329

(5-fluoro-2- (pyrimidin-2- yl)phenyl)((1S,2R,4R)- 2-((5- (trifluoromethyl)pyridin- 2-yl)oxy)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone 330

(2-fluoro-6- (pyrimidin-2- yl)phenyl)((1S,2R,4R)- 2-((5- (trifluoromethyl)pyridin- 2-yl)oxy)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone 331

(2-(2H-1,2,3-triazol-2- yl)phenyl)((1S,2R,4R)- 2-((5- (trifluoromethyl)pyridin- 2-yl)oxy)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone 332

(6-methyl-3-(2H- 1,2,3-triazol-2- yl)pyridin-2- yl)((1S,2R,4R)-2-((5- (trifluoromethyl)pyridin- 2-yl)oxy)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone 333

(3-methyl-2-(oxazol- 2- yl)phenyl)((1S,2R,4R)- 2-((5- (trifluoromethyl)pyridin- 2-yl)oxy)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone 334

(3-methyl-2-(pyridin- 2- yl)phenyl)((1S,2R,4R)- 2-((5- (trifluoromethyl)pyridin- 2-yl)oxy)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone 335

(2-(5-fluoropyrimidin- 2- yl)phenyl)((1S,2R,4R)- 2-((5- (trifluoromethyl)pyridin- 2-yl)oxy)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone 336

(2-fluoro-6-(2H-1,2,3- triazol-2- yl)phenyl)((1S,2R,4R)- 2-((5- (trifluoromethyl)pyridin- 2-yl)oxy)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone 337

(5-methyl-3-(2H- 1,2,3-triazol-2- yl)pyridin-2- yl)((1S,2R,4R)-2-((5- (trifluoromethyl)pyridin- 2-yl)oxy)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone 338

(2-bromo-3- fluorophenyl)((1S,2R, 4R)-2-((5- (trifluoromethyl)pyridin- 2-yl)oxy)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone 339

(3-fluoro-2- (pyrimidin-2- yl)phenyl)((1S,2R,4R)- 2-((5- (trifluoromethyl)pyrazin- 2-yl)oxy)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone 340

(2-methoxy-6- (pyrimidin-2- yl)phenyl)((1S,2R,4R)- 2-((5- (trifluoromethyl)pyrazin- 2-yl)oxy)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone 341

(5-fluoro-2-(2H-1,2,3- triazol-2- yl)phenyl)((1S,2R,4R)- 2-((5- (trifluoromethyl)pyrazin- 2-yl)oxy)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone 342

(4-methyl-2-(2H- 1,2,3-triazol-2- yl)phenyl)((1S,2R,4R)- 2-((5- (trifluoromethyl)pyrazin- 2-yl)oxy)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone 343

(3-methyl-2-(2H- 1,2,3-triazol-2- yl)phenyl)((1S,2R,4R)- 2-((5- (trifluoromethyl)pyrazin- 2-yl)oxy)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone 344

(5-fluoro-2- (pyrimidin-2- yl)phenyl)((1S,2R,4R)- 2-((5- (trifluoromethyl)pyrazin- 2-yl)oxy)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone 345

(2-fluoro-6- (pyrimidin-2- yl)phenyl)((1S,2R,4R)- 2-((5- (trifluoromethyl)pyrazin- 2-yl)oxy)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone 346

(2-(2H-1,2,3-triazol-2- yl)phenyl)((1S,2R,4R)- 2-((5- (trifluoromethyl)pyrazin- 2-yl)oxy)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone 347

(6-methyl-3-(2H- 1,2,3-triazol-2- yl)pyridin-2- yl)((1S,2R,4R)-2-((5- (trifluoromethyl)pyrazin- 2-yl)oxy)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone 348

(3-methyl-2-(oxazol- 2- yl)phenyl)((1S,2R,4R)- 2-((5- (trifluoromethyl)pyrazin- 2-yl)oxy)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone 349

(3-methyl-2-(pyridin- 2- yl)phenyl)((1S,2R,4R)- 2-((5- (trifluoromethyl)pyrazin- 2-yl)oxy)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone 350

(2-(5-fluoropyrimidin- 2- yl)phenyl)((1S,2R,4R)- 2-((5- (trifluoromethyl)pyrazin- 2-yl)oxy)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone 351

(2-fluoro-6-(2H-1,2,3- triazol-2- yl)phenyl)((1S,2R,4R)- 2-((5- (trifluoromethyl)pyrazin- 2-yl)oxy)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone 352

(5-methyl-3-(2H- 1,2,3-triazol-2- yl)pyridin-2- yl)((1S,2R,4R)-2-((5- (trifluoromethyl)pyrazin- 2-yl)oxy)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone 353

(2-bromo-3- fluorophenyl)((1S,2R, 4R)-2-((5- (trifluoromethyl)pyrazin- 2-yl)oxy)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone 354

(2-methoxy-6- (pyrimidin-2- yl)phenyl)((1S,2R,4R)- 2-((5- (trifluoromethyl)pyrimidin- 2-yl)oxy)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone 355

(5-fluoro-2-(2H-1,2,3- triazol-2- yl)phenyl)((1S,2R,4R)- 2-((5- (trifluoromethyl)pyrimidin- 2-yl)oxy)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone 356

(4-methyl-2-(2H- 1,2,3-triazol-2- yl)phenyl)((1S,2R,4R)- 2-((5- (trifluoromethyl)pyrimidin- 2-yl)oxy)-7- azabicyclo[2.2.1]hepta n-7-yl)methanone 357

(3-methyl-2-(2H- 1,2,3-triazol-2- yl)phenyl)((1S,2R,4R)- 2-((5- (trifluoromethyl)pyrimidin- 2-yl)oxy)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone 358

(5-fluoro-2- (pyrimidin-2- yl)phenyl)((1S,2R,4R)- 2-((5- (trifluoromethyl)pyrimidin- 2-yl)oxy)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone 359

(2-fluoro-6- (pyrimidin-2- yl)phenyl)((1S,2R,4R)- 2-((5- (trifluoromethyl)pyrimidin- 2-yl)oxy)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone 360

(2-(2H-1,2,3-triazol-2- yl)phenyl)((1S,2R,4R)- 2-((5- (trifluoromethyl)pyrimidin- 2-yl)oxy)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone 361

(6-methyl-3-(2H- 1,2,3-triazol-2- yl)pyridin-2- yl)((1S,2R,4R)-2-((5- (trifluoromethyl)pyrimidin- 2-yl)oxy)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone 362

(3-methyl-2-(oxazol- 2- yl)phenyl)((1S,2R,4R)- 2-((5- (trifluoromethyl)pyrimidin- 2-yl)oxy)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone 363

(3-methyl-2-(pyridin- 2- yl)phenyl)((1S,2R,4R)- 2-((5- (trifluoromethyl)pyrimidin- 2-yl)oxy)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone 364

(2-(5-fluoropyrimidin- 2- yl)phenyl)((1S,2R,4R)- 2-((5- (trifluoromethyl)pyrimidin- 2-yl)oxy)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone 365

(2-fluoro-6-(2H-1,2,3- triazol-2- yl)phenyl)((1S,2R,4R)- 2-((5- (trifluoromethyl)pyrimidin- 2-yl)oxy)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone 366

(5-methyl-3-(2H- 1,2,3-triazol-2- yl)pyridin-2- yl)((1S,2R,4R)-2-((5- (trifluoromethyl)pyrimidin- 2-yl)oxy)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone 367

(2-bromo-3- fluorophenyl)((1S,2R, 4R)-2-((5- (trifluoromethyl)pyrimidin- 2-yl)oxy)-7- azabicyclo[2.2.1]heptan- 7-yl)methanone 

What is claimed:
 1. A compound of the Formula (I):

or an enantiomer, diastereomer, tautomer, or isotopic variant thereof; or a pharmaceutically acceptable salt or solvate thereof; wherein: R₁ is H; R₂ is H; ring A is:

X is CR₆ and Y is CR₇; R₆ is H or pyrimidinyl; R₇ is H or halo; R₃ is H or pyrimidinyl; R₄ is H or halo; Z is NH; R₅ is optionally substituted pyrazinyl.
 2. The compound of claim 1, wherein n is
 1. 3. The compound of claim 1, wherein R₆ is H.
 4. The compound of claim 1, wherein R₆ is pyrimidinyl.
 5. The compound of claim 1, wherein R₇ is H.
 6. The compound of claim 1, wherein R₇ is halo.
 7. The compound of claim 6, wherein R₇ is F, Cl, or Br.
 8. The compound of claim 1, wherein R₃ is H.
 9. The compound of claim 1, wherein R₃ is pyrimidinyl.
 10. The compound of claim 1, wherein R₄ is H.
 11. The compound of claim 1, wherein R₄ is halo.
 12. The compound of claim 11, wherein R₄ is F, Cl, or Br.
 13. The compound of claim 12, wherein R4 is F.
 14. The compound of claim 1, wherein R₅ is substituted with one trihaloalkyl.
 15. The compound of claim 14, wherein R₅ is substituted with one trifluoromethyl.
 16. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to claim 1 and at least one pharmaceutically acceptable excipient.
 17. A method of treating a disease, disorder, or medical condition, wherein the disease, disorder, or medical condition is a sleep disorder, a metabolic disorder, a neurological disorder, an arrhythmia, acute heart failure, an ulcer, irritable bowel syndrome, diarrhea, gastroesophageal reflux, a mood disorder, post-traumatic stress disorder, a panic disorder, attention deficit disorder, cognitive deficiency, or substance abuse, comprising administering a compound of claim 1 to a patient in need thereof.
 18. The method of claim 17, wherein the disease, disorder, or medical condition is a mood disorder, post-traumatic stress disorder, panic disorder, attention deficit disorder, cognitive deficiency, or substance abuse.
 19. The method of claim 17, wherein the disease, disorder, or medical condition is post-traumatic stress disorder or a panic disorder.
 20. The method of claim 17, wherein the sleep disorder is a sleep-wake transition disorder, insomnia, restless legs syndrome, jet-lag, disturbed sleep, or a sleep disorder secondary to neurological disorders.
 21. The method of claim 17, wherein the metabolic disorder is overweight, obesity, insulin resistance, type II diabetes, hyperlipidemia, a gallstone, angina, hypertension, breathlessness, tachycardia, infertility, sleep apnea, back and joint pain, a varicose vein, or osteoarthritis.
 22. The method of claim 17, wherein the neurological disorder is Parkinson's disease, Alzheimer's disease, Tourette's syndrome, catatonia, anxiety, delirium, or dementia. 